PT2598503E - Cis-tetrahydro-spiro(cyclohexan-1,1'-pyrido[3,4-b]indol)-4-amine derivatives - Google Patents

Description

ΕΡ 2 598 503 / ΡΤ

DESCRIPTION " Cis-tetrahydrospiro (cyclohexane-1,1'-pyrido [3,4-b] indole) -4-amine derivatives " The present invention relates to compounds which act on the nociceptive / ORL-1 receptor system, as well as the -opioid receptor system and which in particular is distinguished by acting selectively in the treatment of chronic pain (including, inter alia inflammatory pain, visceral pain, cancer pain, preferably neuropathic pain) without simultaneously ceasing to exert a marked activity on acute nociceptive pain. In the compounds within the present invention are in particular cis-tetrahydrospiro (cyclohexane-1,1'-pyrido [3,4-b] indole) -4-amine derivatives. Chronic pain can be divided into two large groups. Pathophysiological nociceptive pain is caused by tissue trauma by the excitation of intact nociceptors. This includes, in particular, chronic inflammatory pain. The pain, however, caused by damage and mechanical, metabolic or inflammatory reasons for the nerve itself, are referred to as neuropathic pain. The treatment of chronic pain is a major medical challenge because although the drugs on the market are partly highly effective in cases of acute pain, however, in cases of chronic pain and in particular in cases of neuropathic pain, in many cases satisfactory treatment of pain.

Inflammatory processes are among the most important mechanisms of pain generation. Typical inflammatory pain induced by the release of bradykinin, histamine and prostaglandins with tissue acidification and exudate pressure on the nociceptors. Central nervous system sensitization often occurs as a result, which is manifested in increased neuronal spontaneous activity and stronger responses to stimulation of central neurons (Coderre et al., Pain 1993, 52, 259-285) . These changes in response behavior of central neurons may contribute to the onset of spontaneous pain and to hyperalgesia (increased sensitivity to pain of a noxious or painful stimulus), which are typical of inflamed tissues (Yaksh et al. al., PNAS 1999, 96, 7680-7686).

Anti-inflammatory non-steroidal drugs (NSAIDs or NSAIDs: anti-inflammatory, non-steroidal), which in addition to the analgesic effect, have also been shown to have an anti-inflammatory component (Dickensen, A., International Congress and Symposium Series - Royal Society of Medicine (2000), 246, 47-54). Its application in the case of long-term treatment of chronic pain is however limited in part by some considerable adverse effects, such as gastroenteral ulcer or toxic renal damage. In cases of severe to very severe inflammatory pain (eg in areas of chronic pancreatitis) the use of NSAIDs only leads to and possibly a slight reduction of pain, but because of the increased risk of bleeding they can lead to an excessively high risk. The next step is usually the treatment with -opioids, which in the case of the interested persons can increase the drug dependence in a wide and generalized way (Vercauteren et al., Acta Anaesthesiologica Belgium 1994, 45, 99-105). There is therefore an urgent need for compounds which are very effective in the treatment of inflammatory pain and which have a reduced potential for inducing dependence. Neuropathic pain is caused when the peripheral nerves are damaged by mechanical, metabolic or for inflammatory order reasons. The pain sensations that occur are mainly due to the occurrence of spontaneous pain, hyperalgesia and allodynia (the pain is already being triggered by non-harmful stimuli) (see Baron, Clin Pain 2000, 16 Suppl 2, 12- 20). The causes and manifestations and therefore the needs for the treatment of neuropathic pain are therefore possibly several. They arise as a result of injury or disease of the brain, spinal cord or peripheral nerves. They can be caused by operations (examples are of phantom pain after amputation), spinal cord injuries, strokes, multiple sclerosis, alcohol or drug abuse or other toxins, cancerous disease as well as illnesses 3 ΕΡ 2 598 503 (Such as diabetes, gout, kidney failure or liver cirrhosis as well as infectious diseases such as herpes zoster (or zone), Pfeiffer's glandular fever (or infectious mononucleosis), erythemia, typhoid, diphtheria, HIV, syphilis or Lyme disease). Pain-related experiences have many different signs and symptoms (such as tingling, burning, lancinating or distressing sensations similar to electrical discharges or spontaneous pain or radiating pain) that may change over time, in number, type and intensity.

For the basic pharmacological treatment of neuropathic pain tricyclic and anticonvulsive antidepressants, used as monotherapy or also in combination with opioids, are usually used. These medications usually provide only a certain relief from pain, but in no case provide a complete release of the pain sensation. Often, in order to try and achieve adequate relief of pain levels, dosage levels of the drug are adjusted and increased, often resulting in an increase in side effects. In fact, a higher dosage of an opioid is often necessary, as in the case of satisfactory treatment of acute and neuropathic pains, where the side effects in the treatment have an even more significant significance. Given these conditions, neuropathic pain is now difficult to treat. It is even only partially alleviated by high doses of level 3 opioids (Saudi Pharm, J. 2002, 10 (3), 73-85).

Opioids, which are used in the treatment of neuropathic pain, also usually act against acute pain at the same time. A separation of the treatment of neuropathic pain on the one hand and acute pain on the other hand is not yet possible. Depending on the dose of opioids to use any pain the patient may be suppressed, which can be quite inconvenient. Acute pain therefore fulfills a protective function of the body, which is lost when the sensation of acute pain is significantly affected or suppressed. There is therefore a need to preserve the general perception of pain, while at the same time combating neuropathic pain. 4 ΕΡ 2 598 503 / ΡΤ

Cyclohexane spirocyclic derivatives acting on the Nociceptin / 0RL-1 and -opioid receptor system are known in the art. These compounds are characterized by, among other things, an extremely high structural variability and are useful, among others for the treatment of inflammatory and neuropathic pain. In this context, it is possible, for example, to refer in full to WO 2004/043 967, WO 2005/063769, WO 2005/066183 and WO 2006/108565. There is therefore a need for medicaments that are effective for the treatment of chronic disease pain, in particular neuropathic pain, and which simultaneously affect as little as possible the sensation of acute pain. Where possible, these drugs should contain a dose of active ingredients reduced to such an extent as to enable satisfactory treatment of pain to be achieved without intolerable side effects. The present invention provides novel compounds which are useful and suitable as medicaments and have advantages over medicaments according to the state of the art.

This object is achieved by the object of the present claims. The present invention relates to compounds of the general formula (III)

in which, 5 ΕΡ 2 598 503 / ΡΤ

R1 represents -Η or CH3; R 2 is -H or -halogen; R3 is -H or -halogen; R4 is H, -halo or -OCl-3-alkyl; and R5 is H, -halo or -OCl-3-alkyl; in the form of free bases, or physiologically compatible salts thereof.

It has been found that the compounds of the present invention work surprisingly on the Nociceptin / ORL-1 receptor system and the -opioid system and are particularly effective in the treatment of chronic pain, in particular neuropathic pain, without at the same time allowing suppression of acute pain sensation. In addition, these compounds only exhibit - where this may occur - typical side effects of surprisingly very low opioids and in the range of doses of analgesic effect.

The compounds within the present invention exhibit very high analgesic efficacy in the treatment of chronic pain, in particular neuropathic pain, preferably as a result of poly- or mono-neuropathic diseases.

It has been found that the compounds in doses leading in practice to almost complete suppression of neuropathic pain in mono- or polyneuropathic models, in tests with healthy animals or in healthy tissues of mononeuropathic animals, do not surprisingly have any effect on normal nociception. This means that these compounds cancel out the pathological state (allodynia or hyperalgesia), but at the same time - at most and at most - they only slightly affect the normal sensation of pain. The antinociceptive effect of the compounds on acute pain is therefore insignificant.

The compounds of the present invention thus allow a selective activity against chronic pain, preferably against neuropathic pain, still preferably against mononeuropathic / neuralgic or polyneuropathic pain, preferably against pain in post-herpetic neuralgia or diabetic polyneuropathy, preferably with antinociceptive efficacy 6 ΕΡ 2 598 503 / ΡΤ insignificant in acute pain. This unusual property of the compounds according to the present invention is of fundamental importance for the complete picture of pain therapy.

A first aspect of the present invention relates to compounds of the general formula (III)

Wherein R4 is -H or CH3; R 2 is -H or -halogen, preferably -H or -F, still particularly preferably -H; R 3 is -H or -halogen, preferably one -halogen, particularly preferably -F; R 4 represents H, halogen or -OC 13 alkyl, preferably -H or -OCH 3; R 5 represents H, -halogen or -OC 1 -3 alkyl, preferably -H or -OCH 3 and in the form of free bases, or physiologically compatible salts thereof.

The compounds of formula (III) of phenylacetic acid amide derivatives are used.

The compounds within the scope of the present invention provide a selection of the compounds disclosed in WO 2004/043967, WO 2005/066183 and WO 2006/108565. It has been found that the spiroamines according to the present invention, and which with respect to the two nitrogen atoms present in the cyclohexane ring are cis-configuration (cis-tetrahydrospiro- (cyclohexane-1,1'-pyrido [ 3,4-b] indole) -4-amine), have surprisingly advantages over the other heterocycles. 7 ΕΡ 2 598 503 / ΡΤ

Thus cis spiroamides within the scope of the present invention and in contrast to the other compounds according to WO 2004/043967, WO 2005/066183 and WO 2006/108565 show in animal testing models an excellent activity against chronic pain, particularly pain neuropathic, preferably in the case of pain by diabetic polyneuropathy, but not in its use in the required teurapetic doses have a significant effect against acute pain. Because many side effects of conventional analgesics are associated with the acute pain mechanism, the cis-substituted spirocyclic cyclohexane derivatives of the present invention have a particularly favorable side-effect profile in the field of side effects, particularly adverse side effects typical of opiates.

The compounds within the scope of the present invention are preferably non-chiral; the base body of the general formula (III) does not contain any element of chirality (at the level of the center, axis or plane).

In the compounds according to the present invention, the ring spiro system of isomers in which the substitution pattern in the spiro ring cyclohexane system (not in the indole) is also referred to as cis / trans, Z / E or without / anti. &Quot; cis-trans isomers " are a subset of the stereoisomers (configurational isomers).

In the compounds within the scope of the present invention, each of the two nitrogen atoms of the spiro amine are sin or cis or Z relative to the other:

In a preferred embodiment, the excess of the so-called cis isomer is at least 50%, preferably at least 75%, more preferably at least 90%, more preferably at least 95% and in particular at least 99%.

Suitable methods for separating the isomers (diastereomers) are known to those skilled in the art and to the state of the art. As examples, column chromatography, preparative HPLC and crystallization processes may be mentioned and used. Specific synthetic methods, in which the isomer is produced in excess, are also known in principle by those skilled in the art.

The advantages of the cis-isomer are also particularly surprising, since for the structurally related spiro ethers it is not generally the cis-isomer, but the trans-isomer which has pharmacological advantages (which however are many times different in nature from the benefits provided by the cis spiroamines within the scope of the present invention):

In one preferred embodiment, the compounds within the scope of the present invention are in the form of free bases.

In another preferred embodiment, the compounds of the present invention are in the form of physiologically acceptable salts.

Within the scope of the description, " salt " as any form of the compound in which it takes an ionic form or is charged with electrical charge and is coupled or is in solution with a counter ion (cation or anion). This also comprises the complexes of the compound with other molecules and ions, in particular complexes which are associated through ionic interactions. Preferred salts are those which are physiologically acceptable or compatible, in particular physiologically acceptable salts with anions or acids or also with a salt formed with a physiologically tolerable acid.

Physiologically acceptable salts with anions or acids are the salts of each of the compounds with inorganic or organic acids which are physiologically tolerated - especially when used in humans and / or mammals. Examples of physiologically acceptable salts of specific acids are the salts of: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, saccharic acid, monomethylsebacic acid, 5-oxo-proline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6- benzoic acid, lipoic acid, acetylglycine, acetylsalicylic acid, hippuric acid and / or aspartic acid. Preferably further are the hydrochloride, the citrate and the hemicitrate.

In a preferred embodiment, the compound of the present invention is in the form of a free compound or as a physiologically acceptable salt thereof, but preferably not as the benzenesulfonic acid salt or as the hydrochloric acid salt or a citric.

For purposes of better understanding the present description, the term " halogen " is preferably used herein for the cases of -F, -Cl, -Br or I, preferably -F or -Cl, especially -F.

For purposes of the present description " Ci-3-alkyl " independently represents in each case, linear or branched saturated or mono- or polyunsaturated compounds. Thus " Ci_3-alkyl " includes saturated or unsaturated acyclic hydrocarbon radicals which may be linear or branched, i.e., C1-3 alkanyls, C1-3 alkenyl and C1-3 alkynyl.

Preferred embodiments of the compounds of general formula (III) are compounds of general formula (III): â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ10 ΕΡ 2 598 503 / ΡΤ

(III) in the form of free bases or physiologically tolerated salts thereof, wherein R2 is -H and / or R3 is -F.

Preferably, R 4 and R 5 in either case are either -H or represent -OCH 3.

In a particularly preferred embodiment, the present invention relates to the compound of formula (VI)

in the form of free bases or their physiologically acceptable salts.

The free bases of the compound of formula (VI) may be referred to systematically as (E) -2 ', 3', 4 ', 9' -tetrahydro-N, N-dimethyl-4- (3-fluorophenyl) - 2 '- (2-phenylvinyl) carbonyl spiro [cyclohexane-1,1' (1'H) -pyrido [3,4-b] indole] -4-amine (cis diastereomer) or as (E ) -1 - ((1S, 4S) -4- (dimethylamino) -4- (3-fluorophenyl) -3 ', 4'-dihydrospiro [cyclohexane-1,1'-pyrido [3,4- -b] indole] -2 '(9' H) -yl) -3-phenyl-prop-2- [Î ±] -5,5,8,50-en-1-one. Preferably, this compound exists as a free base, in the form of the hydrochloride, the citrate or hemicitrate.

Particularly preferred compounds within the scope of the present invention are selected from the group consisting of: (E) -2 ', 3', 4 ', 9' -tetrahydro-N, N-dimethyl-4-phenyl-phiphenyl (1 'H) -pyrido [4,3-b] indole] -4-amine (cis diastereomer) or (E) -1 - ((1S, 4-yl) -4- (dimethylamino) -4-phenyl-3 ', 4'-dihio-spiro [cyclohexane-1,1'-pyrido [3,4-b] indole] -2' yl) -3-phenyl-prop-2-en-1-one AMD-lcis (E) -2 ', 3', 4 ', 9'-tetrahydro- N, N -dimethyl-4- (3- (3,4-b] indole] -4-amine (cis diastereomer) or (2-chlorophenyl) -2 '- (2-phenylvinyl) carbonyl spiro [cyclohexane-1,1' E) -1 - ((1S, 4S) -4- (dimethylamino) -4- (3-fluorophenyl) -3 ', 4'-dihydro-spiro [cyclohexane-1,1'-pyrido [ 3-phenyl-prop-2-en-1-one AMD-5cis AMD-6 cis (E) -2 ', 3', 4 ', 9apos; -tetrahydro-N, N-dimethyl-6'-fluoro-5-fluoro-phenyl) -2' - (2-phenyl-vinyl) -carbonyl-spiro [cyclohexane-1,1 ' 1 H) -pyrido [3,4-b] indole] -4-amine (diastereomers cis) or (E) -1 - ((1S, 4S) -4- (d iminoamino) -6'-fluoro-4- (3-fluorophenyl) -3 ', 4'-dihydrospiro [cyclohexane-1,1'-pyrido [3-bindole] -2' (9H) - yl) -3-phenyl-prop-2-en-1-one AMD-8 cis (E) -2 ', 3', 4 ', 9' -tetrahydro- N, N -dimethyl-6'-fluorophenyl- 2 '- (2-phenylvinyl) carbonyl-spiro- [cyclohexane-1,1' (1'H)] - [3,4-b] indole] -4-amine (cis diastereomer) or (E) - 1 - ((1S, 4S) -4- (dimethylamino) -6'-fluoro-4-phenyl-3,4'-dihydrospiro [cyclohexane-1,1'-pyrido [3,4- b ] indole-2 '(9' H) -yl 3-phenyl-prop-2-en-1-one AMD-10 (E) -2 ', 3', 4 ', 9'-tetrahydro- N, N-dimethyl-4- (4-fluorenyl) -2 '- (2-phenylvinyl) carbonyl spiro [cyclohexane-1,1' - (1'Hydroido [3,4- b] indole] - 4-amine (cis diastereomer) or (E) -1 - ((1S, 4S) -4- (dimethylamino) -4- (4-fluorophenyl) -3 ', 4'-dihydrospiro [cyclohexane- (9 'H) -yl) -3-phenyl-prop-2-en-1-one AMD-12cls and the salts thereof and / or physiologically acceptable solvates, in particular the free bases, hydrochlorides, citrates or hemicytrates.

A further aspect of the present invention relates to compounds within the scope of the present invention for use as a medicament. 12 ΕΡ 2 598 503 / ΡΤ

A further aspect of the present invention relates to compounds within the scope of the present invention for use in the treatment of neuropathic and / or chronic pain, wherein preferably the application is made twice a day, or once a day, or less frequently , preferably in the specificities requiring applications no more than once per day.

A further object of the present invention relates to compounds within the scope of the present invention for use in the treatment of chronic pain. Preferably, chronic pain is selected from the group consisting of inflammatory pain, visceral pain, pain due to cancer and neuropathic pain. Neuropathic pain may be of neuralgic / mononeuropathic or polyneuropathic origin.

A further object of the present invention relates to compounds within the scope of the present invention for use in the treatment of pain associated with diabetic polyneuropathy.

Still another object of the present invention relates to compounds within the scope of the present invention for use in the treatment of pain due to post-herpetic neuralgia.

The compounds within the scope of the present invention are suitable for the treatment of neuropathic pain, preferably mononeuropathic / neuropathic or polyneuropathic pain. Preferably in the case of peripheral polyneuropathic pain or central polyneuropathic pain.

Preferably, polyneuropathy or acute polyneuropathic pain (up to four weeks), subacute (4 to 8 weeks) or chronic (more than eight weeks).

Preferably, in the case of polyneuropathy the central nervous system, or the motor, sensory, autonomous, or sensorimotor system are affected. Preferably, the symptoms are distributed symmetrically or asymmetrically. The pain may be mild, moderate, moderately severe, severe or very severe. As a response measure the neuropathic pain scale (NPS) can be used (see BS Galer et al., Neurology 1997, 48, 332-8). 13 ΕΡ 2 598 503 / ΡΤ

Examples of causes of peripheral neuropathic pain include diabetic polyneuropathy, post-herpetic neuralgia, radiculopathy, posttraumatic neuralgia, by means of chemical substances, for example chemotherapy-induced polyneuropathy, phantom limb pain, complex regional syndrome, sensory polyneuropathy induced by HIV (or HIV) and alcoholic polyneuropathy. Examples of causes of central polyneuropathic pain are compressive myelopathy due to narrowed channel, post-traumatic spine pain, stroke pain, post-ischemic myelopathy, radiation-induced myelopathy, multiple sclerosis-induced myelopathy, and HIV-induced myelopathy.

In one preferred embodiment neuropathies causing neuropathic pain are associated with a disease selected from the group consisting of diabetes mellitus, vasculitis, uremia, hypothyroidism, alcohol abuse, post-herpetic neuralgia, idiopathic neuropathy, chronic inflammatory demyelinating neuropathy , multifocal motor neuropathy, hereditary polyneuropathy, Guillain-Barré syndrome, intoxication [eg by alcohol, heavy metals (especially in cases of Pb, Hg, As, hydrocarbons after chemotherapy with cytostatics], porphyria, infectious diseases, cancerous diseases [e.g. Myeloma, amyloid, leukemia, lymphomas], pernicious anemia, vitamin E deficiency, Refsum's disease, Bassen-Kornzweig syndrome, Fabry's disease, vasculitis and amyloidosis. Diabetic polyneuropathy and post-herpetic neuralgia are particularly preferred. In the case of an infectious disease, it is preferably selected from the group consisting of mononucleosis, ehrlichiosis, typhus, diphtheria, leprosy, HIV, syphilis and Lyme disease.

Preferably, they are polyneuropathic pain of pains which are caused by a polyneuropathy, as defined by ICD-10 (International Classification of Diseases and Related Health Problems, WHO edition, preferably 2008 version).

A further object of the present invention relates to compounds within the scope of the present invention for use in treating anxiety, stress and stress related syndromes, depression, epilepsy, Alzheimer's disease, dementia, senile dementia, general cognitive dysfunctions, memory and learning disorders (such as nootropic), withdrawal symptoms, alcohol and / or drug abuse and / or drug addiction, sexual dysfunction, cardiovascular disease, hypotension, hypertension , tinnitus, pruritus, migraine, deafness, lack of intestinal motility, eating disorders, anorexia, obesity, locomotor disorders, diarrhea, cachexia, urinary incontinence or as a muscle relaxant, anticonvulsant or anesthesia or for the co-administration of a treatment with an opioid analgesic, or with an anesthetic, for diuresis or anti-natriuresis, anxiolysis, to modulate movement activity, for modulation the release of neurotransmitters and the treatment of neurodegenerative diseases associated therewith, for the treatment of withdrawal symptoms and / or to reduce the addictive potential of opioids.

The compounds within the scope of the present invention may be used in methods of treatment, in particular one of the above indications, in cases of non-human mammal or being human that or need treatment of chronic pain, preferably neuropathic pain, preferably in addition to diabetic polyneuropathy or post-herpetic neuralgia, by means of a single daily dose therapeutically required of a compound within the scope of the present invention, or by means of a dosage form within the scope of the present invention, preferably at the same time , its administration does not cause significant suppression of the sensation of acute nociceptive pain and / or that there are no significant side effects typical of opioids, especially and essentially without respiratory depression and / or non-constipation and / or non-urinary retention and / or absence of nausea and / or without vomiting and / or without hypotension and / or episodes of bradycardia and / or no addictive effect and / or no dependence and / or no euphoria and / or no depression and / or no sedation and / or no dizziness.

The compounds within the scope of the present invention may also be used in methods of treatment, in particular one of the aforementioned indications, in cases of non-human or human mammal requiring treatment of chronic pain of preferably neuropathic pain, preferably pain by diabetic polyneuropathy or post-herpetic neuralgia by administration of a daily dose X of a compound within the scope of the present invention, or a dosage form within the scope of the present invention, wherein preferably and not simultaneously there is significant suppression of acute nociceptive pain sensation and / or no significant side effects typical of opioids occur, there being in particular and essentially no respiratory depression and / or constipation and / or urinary retention and / or occurrence of nausea and / or vomiting and / or hypotension and / or episodes of bradycardia and / or addictive effects and / or addiction and / or euphoria and / or depression and / or sedation and / or dizziness; wherein the daily dose X is selected from the group consisting of the values: 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0 , 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7 , 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 mg.

A further object of the present invention relates to compounds according to the present invention with affinity for the -opioid receptor and the ORL-1 receptor, which in the treatment of neuropathic pain, preferably in the rat, is preferred as mononeuropathic pain in the Chung model, are characterized as having a significant effect when using a dose corresponding to half the maximal effect ED5on, and • in the treatment of acute pain, preferably in rats, preferred in Tail-Flick-Test ), at doses that even with a factor 5 times greater than that of ED50n, have substantially no significantly efficacious results.

Accordingly, the compounds within the scope of the present invention when administered at these doses of the half-maximal efficacy ED50n, which is defined in terms of the efficacy of the compound against neuropathic pain, and even when administered in doses with a factor of 5-fold than ED50, at most and at most have a perfectly negligible antinociceptive effect in acute pain cases, preferably in the rat tests, preferably still in Tail-Flick-Test.

In a preferred embodiment, this is the case in which the neuropathic pain of mononeuropathic pain or neuralgic pain is preferably a pain resulting from post-herpetic neuralgia. In another preferred embodiment, it is the case in which polyneuropathic pain is preferably pain associated with diabetic polyneuropathy.

Preferably the compounds within the scope of the present invention, even when used in a dosage with factors of 10, 20, 30, 40 or 50, more preferably still by factors of 75, 100, 125, 150 or 175, still more preferably by factors 200, 300, 400 or 500, preferably even by factors of 600, 700, 800 or 900, and in particular, even at a factor of 1000 times greater than the efficiency dose corresponding to half the maximum ED50n, in the treatment of acute or nociceptive pain, has substantially no significant effect. The efficiency dose ED5on corresponding to half the maximum is known to those of skill in the art. It is preferably defined as the dose for which 50% of the maximum therapeutic effect is achieved with respect to the treatment of neuropathic pain. Therefore, a dose value corresponding to half that maximum in ED50a efficiency can be defined as the dose for which 50% of the maximum therapeutic effect is achieved with respect to the treatment of acute pain. The compounds within the scope of the present invention are, however, defined by ED50n but not ED 50a values.

Appropriate methods for evaluating the efficacy of a drug in the treatment of neuropathic pain and determination of the efficiency dose value corresponding to half the maximum ED50 for the treatment of neuropathic pain are known to those skilled in the art and to the state of the art. This also applies to the study of the efficacy of a drug against acute pain. The determination of such values can be performed, for example, on animal models (for example, with mice or rats), where: • mononeuropathic pain can be investigated according to

Chung (SH Kim, JM Chung, Pain, 1992, 50 (3), 355-63) and Bennett (GJ Bennett, YK Xie, Pain 1988, 33 (1), 87-107), • pain by diabetic polyneuropathy can be performed according to streptozotocin (STZ) -induced diabetes (EK Joseph, JD Levine, Neuroscience, 2003; 120 (4): 907-13) and acute pain can be determined according to the so-called Tail-Flick- Test (D 'Amour and Smith, J. Pharm Exp Exp. Ther. 72, 1941, 74-9)

Preferably, the determination is made by animal testing, that is, with respect to the efficacy against neuropathic pain as efficacy against mononeuropathic pain in the rat according to the Chung model and as regards its efficacy against acute pain in rats according to the tail withdrawal test, preferably, respectively, as described in the experimental part.

Accordingly, the compounds within the present invention preferably have an affinity for the opioid receptor and the ORL-1 receptor, which in rat are significantly effective in the treatment of mononeuropathic pain according to the Chung model and are thus characterized by an efficiency dose corresponding to half the maximum ED50n, and are not significantly effective in the treatment of acute pain according to the tail withdrawal test at a dose which is 5 times greater than ED50n. The evaluation of the experimental results in terms of statistically significant differences between the respective dosage groups and vehicle control groups was preferably performed by repeated-measures analysis of variance (repeated measures ANOVA) as described in post hoc analysis according to 18 ΕΡ 2 598 503 / ΡΤ

Bonferroni, preferably as described in the experimental section. Here, we establish a level of significance p <0.05. The dimensions of the groups are generally n = 10.

In principle, comparative measurements of analgesic efficacy against neuropathic pain and acute nociceptive pain in humans may also be made, which, however, among other things, because they involve ethical considerations, are therefore less preferred. The study of efficacy against neuropathic pain, ie in patients suffering from neuropathic pain, may then be performed according to Hansson P, Backonja M, Bouhassira D. (2007), Usefulness and limitations of quantitative sensory testing: clinicai and research application in neuropathic pain States. Pain. 129 (3): 256-9. The study of efficacy against acute pain can be done according to Posner J, Telekes A, Crowley D, Phillipson R, Peck AW. (1985), Effects of an opiate on cold-induced pain and the CNS in healthy volunteers. Pain. 23 (1): 73-82.

It has been found that the compounds within the present invention are characterized by a surprisingly very favorable side effect profile when compared to conventional level 3 opioids. Thus, even when administered in therapeutically effective doses as especially required for the treatment of neuropathic pain , no, or at most only some, but not very pronounced, side effects typical of opiates were observed, such as for example respiratory depression, constipation, urinary retention, nausea, vomiting, hypotension, bradycardia, addictive effects, euphoria, depression, sedation and dizziness. To date, there has been a fairly low incidence of typical side effects of opioids such as respiratory depression, constipation, hypotension, bradycardia, impairment of motor coordination ability (as a measure of side effects of the nervous system central), as well as physical and psychic dependence.

In a preferred embodiment, the compounds within the scope of the present invention when administered at the dose η 2 598 503 / ΡΤ equivalent to half maximal efficiency ED50n, which is defined in terms of the efficacy of the compound against neuropathic pain, and preferably still , at a dose which is 5-fold higher than ED50, without significant respiratory depression as a side effect, preferably in the rat, more preferably in the blood gas analysis model. Preferably, the compounds within the scope of the present invention, even at a dose which is a factor of 10, 20, 30, 40 or 50, more preferably a factor of 75, 100, 125, 150 or 175, even more than preference for a factor of 200 times greater than the dose corresponding to half the maximum efficiency ED50n, does not present any significant respiratory depression as a side effect.

Appropriate methods for studying respiratory depression induced by drugs or active substances are well known to the skilled person and to the state of the art. Preferably, the analysis is performed on a blood gas analyzer model in the rat as a change in arterial O 2 and partial CO 2 pressures. The analysis of the experimental results obtained with respect to the statistically significant differences between the respective dosage groups and the vehicle control group is preferably performed using the analysis of the variance factor (one-way ANOVA) as well as the post hoc analysis according to Dunnett, preferably, as described in the experimental part. Here, the significance level set is p &lt; 0.05. The dimensions of the groups are generally from n = 6. More details on this model of animal testing are also referred to in the experimental section.

In a preferred embodiment, the compounds within the scope of the present invention when administered at the dose level corresponding to half the maximum efficiency ED50n, which is defined in terms of the efficacy of the compound against neuropathic pain, and more preferably, at a dosage which is a factor 5 fold greater than ED50n, no significant constipation effect is observed as a side effect, preferably in the rat, more preferably in the char pass test. Preferably the compounds within the scope of the present invention, even at a dosage preferably of a factor of 10, 20, 30, 40 or 50, plus 20 and 598 503 / ΡΤ preferably by a factor of 75, 100, 125, 150 or 175, even more preferably by a factor of 200, 300, 400 or 500, preferably still by a factor of 600 times greater than the dose corresponding to half the maximum efficiency ED50n does not show any significant constipation as a side effect.

Appropriate methods for testing constipation or constipation induced by active substances are known to those skilled in the art and to the state of the art. Preferably, the analysis is carried out in a charcoal passage model in the rat test, such as the change in the speed of gastrointestinal transit. The evaluation of the experimental results obtained with respect to the statistically significant differences between the respective dosage groups and the vehicle control group is preferably performed using the analysis of the variance factor (one-way ANOVA) as well as a post-analysis hoc according to Dunnett, preferably, as described in the experimental part. Here, the significance level set is p &lt; 0.05. The dimensions of the groups are generally n = 10. More details on this model with animal tests are also referred to in the experimental section.

In a preferred embodiment, the compounds within the scope of the present invention when administered at the dose corresponding to half the maximum efficiency ED50, which is defined in terms of the efficacy of the compound against neuropathic pain, and preferably at a 5 fold factor greater than ED50n, shows no significant hypotension as a side effect, preferably using awakened rabbits, preferably in the circuit model in conscious rabbits, by telemetry. Preferably, the compounds within the scope of the present invention, even at doses having a factor of 10, 20, 30, 40 or 50, more preferably by a factor of 75, 100, 125, 150 or 175, more preferably still by a factor 200-fold higher than the dose corresponding to half the maximum ED50n efficiency, do not present significant hypotension values as a side effect. 21 ΕΡ 2 598 503 / ΡΤ

Suitable methods for investigating hypotension induced by active substances are known to those skilled in the art and to the state of the art. Preferably, the analysis is performed in a closed loop model with telemetry-aware rabbits, measuring the change in blood pressure (systolic, diastolic, and mean). The evaluation of the experimental results obtained with respect to the statistically significant differences between the respective dosage groups and the vehicle control group is preferably performed using the analysis of the variance factor (one-way ANOVA) as well as a post-analysis hoc according to Dunnett, preferably, as described in the experimental part. Here, the level of significance defined is p &lt; 0.05. The dimensions of the groups studied are generally n = 6. More details on this model of animal testing are also referred to in the experimental section.

In a preferred embodiment, the compounds within the scope of the present invention when administered at the dose corresponding to half the maximum efficiency ED50, which is defined in terms of the efficacy of the compound against neuropathic pain, and preferably at the dose which is one factor 5-fold higher than ED50n, shows no significant bradycardia as a side effect, preferably in the waking rabbit, preferably in the closed loop model of telemetry-scanned rabbits. Preferably, the compounds within the scope of the present invention, even at a dose which is of a factor of 10, 20, 30, 40 or 50, more preferably by a factor of 75, 100, 125, 150 or 175, still more preferably by a factor 200 times greater than that of the relative dose to half the maximum efficiency ED5on, does not present any significant bradycardia as a side effect.

Suitable methods for investigating bradycardia induced by active substances are known to those skilled in the art and to the state of the art. Preferably, the analysis is performed on a conscious rabbit closed loop model tracked by telemetry by measuring their heart rate changes. The evaluation of the experimental results obtained in what refers to the statistically significant differences between the respective dosage groups and the vehicle control group is preferably performed using the analysis of the variance factor (ANOVA of one pathway) as well as a post hoc analysis according to Dunnett, preferably, as described in the experimental part. Here, the significance level set is p &lt; 0.05. The dimensions of the groups are generally n = 6. More details on this model of animal testing are also referred to in the experimental section.

In a preferred embodiment, the compounds within the scope of the present invention when administered at the dose relative to half the maximum efficiency ED50n, which is defined in terms of the efficacy of the compound against neuropathic pain, and preferably at doses with a 5-fold factor greater than ED50n, does not present any significant disturbance of motor coordination ability (as a measure of side effects in the central nervous system), as a side effect, preferably in the rat, more preferably in the RotaRod test. Preferably, the compounds within the scope of the present invention, even at dosages preferably by factors of 10, 20, 30, 40 or 50, more preferably by factors of 75, 100, 125, 150 or 175, still more preferably by factors of 200, 300, 400 or 500, preferably even by factors of 600, 700, 800 or 900, and in particular by a factor 1000 times higher than the dose corresponding to half the maximum efficiency ED50n, does not present any significant disturbance of coordination capacity (as a measure of side effects in the central nervous system) as a side effect.

Appropriate methods for studying a disorder of motor coordination ability induced by active substances are known to those skilled in the art and the state of the art. Preferably, the investigation takes place in a RotaRod model in mice (analogous to Kuribara H., Higuchi Y., Tadokoro S. (1977), Effects of central depressants on Rota-Rod and traction performance in mice, J. Pharmacol 27, 117-126.) By measuring the changes in the ability to walk on a rotating rod. The evaluation of the experimental results obtained with respect to the statistically significant differences between the respective 23 ΕΡ 2 598 503 / ΡΤ respective dosage groups and the vehicle control group is preferably performed using the analysis of variance factor (one-way ANOVA ) as well as a post hoc analysis according to Dunnett, preferably, as described in the experimental part. Here, the significance level set is p &lt; 0.05. The dimensions of the groups are generally n = 10. More details on this model of animal testing are also referred to in the experimental section.

In a preferred embodiment, the compounds within the scope of the present invention when administered at the dose corresponding to half the maximum efficiency ED50, which is defined in terms of the efficacy of the compound against neuropathic pain, and preferably, in dosages which is one factor 5 times greater than ED5on, there is no significant physical dependence or withdrawal symptoms, as side effects, preferably in the rat, more preferably in the jumping tests. Preferably, the compounds within the scope of the present invention, even when in dosages preferably having factors of 10, 20, 30, 40 or 50, more preferably factors of 75, 100, 125, 150 or 175, still more preferably factors of 200 , 300, 400 or 500, and preferably even by factors of 600, 700, 800 or 900, and in particular by a factor 1000 times higher than the dose corresponding to half the maximum efficiency ED50n, does not present any physical dependence significant or withdrawal symptoms as a side effect.

Appropriate methods for investigating an active substance-induced physical dependence are known to the skilled person and to the state of the art. Preferably the investigation is performed according to the model of occurrence of jumps in the rat (analogous to Saelens JK, Arch Int Pharmacodyn 190: 213-218, 1971) as the withdrawal induced by naloxone. The evaluation of the experimental results in terms of statistically significant differences between the respective dosage groups and the vehicle control groups is preferably done by the Fisher exact test for the parameter: &quot; number of animals with withdrawal symptoms &quot; , as well as by means of the Kruskal-Wallis test 24 ΕΡ 2 598 503 / ΡΤ for the parameter: &quot; skip frequency &quot;, preferably as described in the experimental part. In these cases, the significance level established in each one is p &lt; 0.05. The dimensions of the groups are generally n = 12. More details on this model of animal testing are also referred to in the experimental section.

In a preferred embodiment, the compounds within the scope of the present invention when administered at the dose corresponding to the maximum efficiency ED50n, which is defined in terms of the efficacy of the compound against neuropathic pain, and preferably even at a dose which is one factor 5-fold greater than ED50n, shows no significant psychological dependence or addictive effect as a side effect, preferably in the mouse, preferably by means of the conditioned position preference test. Preferably, the compounds within the scope of the present invention, even at a dosage preferably of a factor of 10, 20, 30, 40 or 50, more preferably by a factor of 75, 100, 125, 150 or 175, still more preferably by a factor of 200, 300, 400 or 500, and still more preferably by a factor of 600, 700, 800 or 900 and particularly preferably by a factor 1000 times higher than the dose corresponding to the maximum efficiency ED50, has no psychological dependence or dependence with significant addictive effects as a side effect.

Appropriate methods for investigating a psychological dependence or addiction with addictive effects induced by active substances are well known to the skilled person and to the state of the art. Preference is given to an assay using a conditioned preference position in mice, preferably as described in Tzschentke, TM, Bruckmann, W. and Friedrichs, F. (2002) Lack of sensitization during place conditioning in rats is consistent with the low abuse potential of tramadol. Neuroscience Letters 329, 25-28. The evaluation of the experimental results obtained with respect to the statistically significant differences in the preference of the animals for the active ingredient or for the vehicle is preferably performed by means of the paired t-test. Here the level of significance was set at p <0.05. The dimensions of the groups of 25 Ρ Ρ 2 598 503 / ΡΤ are generally n = 8 Further details on this model of animal testing are published in the methods described in Tzschentke, TM, Bruckmann, W. and Friedrichs, F. (2002) , Neuroscience Letters 329, 25-28.

The compounds within the present invention are suitable for the treatment of chronic pain, preferably neuropathic pain, preferably against mononeuropathic / neuralgic pain or polyneuropathic pain, more preferably still against pain in post-herpetic neuralgia or diabetic polyneuropathy.

Definitions of the various forms of chronic pain are known to the person skilled in the art. In this context, for example, Merskey H., Bogduk N. Classification of chronic pain. Seattle: IASP Press 1994, Bennett G.J., Anesth Analg. 2003, 97, 619-20, as well as

Backonja M.M., Anesth Analg. 2003, 97, 785-90.

For the purpose of the description, chronic pain is preferably defined as existing painful symptomatology for an extended period of time (generally at least 3, 4, 5 or 6 months) which also lasts beyond the normal times of healing and treatment. Preferably, neuropathic pain is defined as the pain or sensory phenomenon that is caused by injury, disease or dysfunction of the central or peripheral nervous system. For the purposes of the present disclosure, acute pain is preferably defined as an unpleasant sensory and emotional experience associated with possible acute or potential tissue damage or described in terms of such damages (see Definition of International Association for the Study of Pain IASP)).

The compounds within the scope of the present invention preferably have a Ki value at the receptor -opioid of at most 1000 nm, more preferably at most 500 nm, even more preferably at least 100 nM, more preferably at most 50 nm, and in particular preferably no more of 25 nm.

Methods for determining Ki value at the receptor-opioid are known to those skilled in the art. Preferably, the determination is effected by a homogenous approach in microtiter plates. For this purpose, a series of dilutions of each of the substances to be tested with a receptor membrane preparation (15-40 μg protein per 250 μl incubation mixture) of CHO-K1 cells express the human receptor-opioid (RB-HOM receptor membrane preparation from NEN, Zaventem, Belgium) in the presence of 1 nmol / l of the [3 H] -naloxone radioactive ligand (NET719, from NEN, Zaventem, Belgium) as well as 1 mg beads WGA-SPA (Agglutinin wheat germ SPA beads from Amersham / Pharmacia, Freiburg, Germany) in a total volume of 250 μl for 90 minutes in incubation at room temperature. As the incubation buffer, 50 mmol / l of Tris-HCl supplemented with 0.05% by weight of sodium azide and 0.06% by weight of bovine serum albumin is preferably used. For the determination of nonspecific binding effected, even more preferably 25 pmol / l of naloxone is added. After the completion of the ninety minute incubation period, the microtiter plates are preferably centrifuged for 20 minutes at 1000Â ° C and the radioactivity measured on a beta-counter (Micro Beta Trilux, PerkinElmer Wallac, Freiburg, Germany). The percentage displacement of the radioactive ligand from its binding to the human-opiate receptor is thus determined at a concentration of test substances of preferably 1 æmol / l, and expressed as percent inhibition (% inhibition) of the specific binding. Based on the percent displacement at different concentrations of the compounds to be tested, the IC50 inhibitory concentrations that cause a 50 percent displacement of the radioactive ligand can be calculated. By conversion using the Cheng-Prusoff equation the Ki values for the test substances can be calculated.

The compounds within the present invention preferably have a Ki value at the ORL-1 receptor of at most 500 nm, more preferably at most at 100 nm, more preferably at most 50 nm, and in particular preferably at most at 10 nm.

Methods for determining the Ki value at the ORL-1 receptor are known to those skilled in the art and to the state of the art. Preferably, the determination is performed in a 3H-nociceptin / Orphanin FQ receptor binding assay with recombinant CH0-0RL1 cell membranes. This test system is preferably performed under the proposed method according to Ardati et al. (Mol Pharmacol., 51, 1997, pp. 816-824). The 3 H-nociceptin / CF orphanin concentration is preferably in these 0.5 nM experiments. The binding assay is preferably carried out in each case with 20 μg of membrane protein in each case in a 200 μ ensaio assay in 50 mM Hepes, pH 7.4, 10 mM MgCl 2 and 1 mM EDTA. The binding to the ORL1-Receptor will preferably be determined using in each case 1 mg WGA-SPA beads (Amersham-Pharmacia, Freiburg), by means of a 1 hour incubation in assays at ambient temperature and finally measured in a counter Trilux scintillations (Wallac, Finnland).

Appropriate methods for the synthesis of the compounds within the scope of the present invention are in principle known to the person skilled in the art. The following are preferred routes or synthetic routes: Synthesis of the element or constituent block ketone E:

Phase 1 (to obtain B)

The structures of formula B can be prepared by reacting ketones A with amines and Z-H acid reactants. Suitable Z-H reactants are for example hydrogen cyanide, 1,2,3-triazole, benzotriazole or pyrazole. A particularly preferred route for compounds of structure B is the reaction of ketones with metal cyanides and the corresponding amine in the presence of acid, preferably in an alcohol, at temperatures of -40 to 60øC, preferably at room temperature, with cyanides of alkali metals in methanol. A still more particularly preferred route for compounds of structure B is the reaction of ketones with 1,2,3-triazole and the corresponding amine in the presence of dehydration conditions, preferably using a distiller to separate the water at an elevated temperature in a solvent inert, or using a molecular sieve or other means of excision. Analogously B structures may be introduced with benzotriazole or pyrazole instead of triazole groups.

Step 1 (to obtain Q) Preparation of the imines of formula Q from ketones A is achieved based on the state of the art.

Stage 2 (to obtain B)

Acetals C may generally be obtained by substituting suitable starting groups Z in the structures of formula B. Suitable starting groups are preferably cyano groups; 1,2,3-triazol-1-yl groups. Other suitable starting groups are 1H-benzo [d] [1,2,3] triazole-1-yl groups and pyrazol-1-yl groups (Katritzky et al., Synthesis 1989, 66-69). A particularly preferred route for compounds of structure C is the reaction of aminonitriles B (Z = CN) with the corresponding organometallic compounds, preferably Grignard compounds, preferably in ethers, preferably at room temperature. Organometallic compounds are either either commercially available or can be prepared according to the current state of the art. A particularly preferred route for compounds of structure C is the reaction of aminotriazoles B (Z = triazole) with the corresponding organometallic compounds, preferably Grignard compounds, preferably in ethers, preferably at 29Â ° C 598 503 / . The organometallic compounds are either commercially available or may be prepared generally according to the state of the art.

Phase 2 (to obtain Q)

Aminoacetals C, with a maximum of one substituent on the nitrogen atom, may in principle, according to methods known to those skilled in the art, be obtained by addition of nucleophilic carbons to Q imines, preferably organometallic compounds, in inert solvents, more preferably with Grignard reagents or organolithium compounds, preferably in ethers, preferably at temperatures of 100 ° C to room temperature.

Phase 4/5:

The compounds of formula E may be liberated by acid deprotection from the corresponding acetals or C or its salts D by a process generally well known in the art. In this case X is selected from the group consisting of alkyl, alkyl / allylidene, with aryl- or alkyl- (saturated / unsaturated) -alkylidene.

Preparation of C (R * H) from Ca (R 1 = -H)

Aminoacetals Ca with a maximum of one substituent on the nitrogen atom may in principle according to procedures well known to those skilled in the art, such as by reductive amination, to be converted to the acetal amino acids C corresponding with one or two other substituents on the nitrogen atom.

The necessary ketone intermediate E may be prepared, for example, by the following three different routes: (1) via aminonitrile, (2) imine route and (3) via triazole. (1) Via aminonitrile:

In the amino nitrile pathway, as described in the following synthesis scheme, amino nitrile Ba is synthesized from a precursor of ketones A, which is subsequently converted into the constituent blocks C or D and subsequently E, using a nucleophile MR3 . This synthetic route has already been described and applied in WO 2004/043967.

(2) Via imine:

In the imine pathway as described in the following scheme, the imine Q is synthesized from a precursor of ketones A, which is subsequently converted into the constituent blocks C or D and subsequently E using a nucleophile MR3. The required constituents of imine Q can be prepared by one of the methods known to those skilled in the art (Layer, Chem Rev., 1963, 8, 489-510). For the addition of the MR3 metal organo compounds to the imine Q, processes known from the methods described in the literature (for example, Maddox et al., J. Med. Chem., 1965, 8, 230-235, Kudzma et al., J. Med. Chem, 1989, 32, 2534-2542). Phases 3, 4 and 5 have a pathway analogous to that of the amino nitrile pathway. 31 ΕΡ 2 598 503 / ΡΤ

(3) Via triazole:

In the triazole pathway, as described in the following scheme, a triazole Bb is synthesized from a precursor of ketones A, which is subsequently converted into the constituent blocks C or D, and later using a nucleophile MR3. The conditions can be found in the cited literature: (a) Katritzky et al. Synthesis, 1992, 1295-1298. (b) Prashad, et al., Tetrahedron Lett. 2005, 46, 5455-5458.

E D 32 ΕΡ 2 598 503 / ΡΤ Synthesis of spiroamines (AMN) 32 ΕΡ 2 598 503 / ΡΤ

H-type tryptamines can be used in reactions of the Pictet-Spengler reaction type with ketones E with the addition of at least one reagent selected from the group of acids, acid anhydrides, esters, weakly acid salts or Lewis to form products of the formula AMN.

It is preferred to use at least one reagent from the group of carboxylic acids, phosphoric acids or sulfonic acids or their respective anhydrides, trialkylsilyl carboxylic acid ester, acidic reagent salts, mineral acids or Lewis acids selected from the group consisting of trifluoride (III) chloride, titanium tetrachloride, aluminum (III) chloride, or with the addition of at least one transition metal salt, preferably with the addition of at least one transition metal triflate ( transition metal trifluoromethanesulfonates), especially preferably with the addition of at least one transition metal trifluoromethanesulfonate selected from the group consisting of scandium (III) trifluoromethanesulfonate, ytterbium (III) trifluoromethanesulfonate, indium trifluoromethanesulfonate (III ), optionally with the addition of Celite with reagents bound to the solid phase or high or low temperature, with or without the use of microwave irradiation, optionally in a suitable solvent or mixture of solvents, such as for example chlorinated or non-chlorinated, then preferably in aromatic hydrocarbons, acetonitrile; in ethereal solvents, preferably in diethyl ether or THF, or in nitromethane, in suitable cases, also in alcohols or water. Particularly preferred herein to be used are para-toluenesulfonate of 33 593 503 / ΡΤ pyridinium, phosphorus pentoxide in the presence of celite, boron trifluoride etherate, trifluoroacetic acid, tetraisopropyl ester ortho-ethanic acid with trifluoro- acetic acid, trifluoromethanesulfonic acid trimethylsilyl ester, trifluoromethanesulfonic acid, methanesulfonic acid, trifluoroacetic acid, acetic acid, phosphoric acid, polyphosphoric acid, polyphosphate ester, p-toluenesulfonic acid, hydrochloric acid HCl gas, sulfuric acid together with acetate buffer solution , tin tetrachloride.

Again, the conditions set forth in the following examples are preferred.

The compounds of the general formulas H and E are either commercially available or their preparation can be provided based on the knowledge according to the state of the art or on the basis of those skilled in the art. Particularly relevant for this purpose are the following works: Jirkovsky et al., J. Heterocycl. Chem., 12, 1975, 937-940; Beck et al., J. Chem. Soc. Perkin 1, 1992, 813-822; Shinada et al., Tetrahedron Lett., 39, 1996, 7099-7102; Garden et al., Tetrahedron, 58, 2002, 8399-8412;

Lednicer et al., J. Med. Chem., 23, 1980, 424-430; Bandini et al. J. Org. Chem. 67, 15; 2002, 5386-5389; Davis et al., J. Med. Chem. 35, 1, 1992, 177-184; Yamagishi et al., J. Med. Chem. 35, 11, 1992, 2085-2094; Gleave et al .;

Bioorg.Med.Chem.Lett. 8, 10, 1998, 1231-1236; Sandmeyer,

Helv.Chim. Acta; 2; 1919; 239; Katz et al. ; J. Med. Chem. 31, 6, 1988; 1244-1250; Bac et al. Tetrahedron Lett. 1988, 29, 2819; Ma et al. J. Org. Chem. 2001, 66, 4525; Kato et al. J. Fluorine Chem. 99, 1, 1999, 5-8. Synthesis of spiroamides (AMD)

AMN AMD 34 ΕΡ 2 598 503 / ΡΤ

The compounds of the general formula AMN may be used in reactions with carboxylic acids in at least one solvent, preferably selected from the group consisting of dichloromethane, acetonitrile, dimethylformamide, diethyl ether, dioxane and tetrahydrofuran, with the addition of at least one coupling reagent, preferably selected from the group consisting of carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodide (Mukaiyama reagent), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide (EDCI) (TBTU), N, N'-dicyclohexylcarbodiimide (DCC), and 1-benzo-triazolyloxy-tris-hexafluorophosphate (dimethylamino) phosphonium bromide (BOP), optionally in the presence of at least one inorganic base, preferably selected from the group consisting of potassium carbonate and cesium carbonate, or an organic base, preferably selected from the group which consists of tr ethylamine, diisopropylethylamine and pyridine, and optionally with the addition of 4- (dimethylamino) pyridine or 1-hydroxybenzotriazole at a temperature preferably from 25 ° C to 150 ° C, optionally under microwave irradiation, to give compounds of formula general AMD.

The compounds of the general formula AMN may be reacted with acid anhydrides and carboxylic acid chlorides in at least one solvent, preferably selected from the group consisting of dichloromethane, acetonitrile, dimethylformamide, diethyl ether, dioxane and tetrahydrofuran, optionally in the presence of at least one inorganic base, preferably selected from the group consisting of potassium carbonate, and cesium carbonate, or an organic base, preferably selected from the group consisting of triethylamine, diisopropylethylamine and pyridine, and, optionally, with the addition of 4- (dimethylamino) pyridine or 1-hydroxybenzotriazole, at a temperature range preferably from 25 ° C to 150 ° C, optionally under microwave irradiation, to give compounds of the general formula AMD.

For further details for the synthesis of the compounds within the scope of the present invention, in particular in the synthesis of the building blocks of the appropriate starting reagents, further details can be found in the referenced documents WO 2004 / 043967, WO 2005/063769, WO 2005/066183, WO 2006/018184, WO 2006/108565, WO 2007/124903 and WO 2008/009416. One skilled in the art will recognize that the building blocks of reagents suitable for the synthesis of the compounds within the scope of the present invention can be prepared analogously to the methods disclosed in these references and synthetic schemes as well as the embodiments.

The compounds within the scope of the present invention may for example act on the cause of various diseases related to ORL1 and -opioid receptors, such that they are themselves in active substance (medicament) in pharmaceutical compositions.

A further object of the present invention relates to a pharmaceutical composition containing a physiologically acceptable carrier and at least one compound within the scope of the present invention.

Preferably, the composition within the scope of the present invention is solid, liquid or pasty; and / or contains the compound within the scope of the present invention in an amount of 0.001 to 99% by weight, preferably 1.0 to 70% by weight, based on the total weight of the composition. The pharmaceutical composition within the scope of the present invention may contain, if necessary, suitable additives and / or auxiliaries and / or optionally other additional active ingredients.

Examples of suitable physiologically acceptable carriers or vehicles, additives and / or auxiliary substances are fillers, fillers, solvents, diluents, colorants and / or binders. These substances are known to those skilled in the art and to the state of the art (see HP Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete, Editio Cantor Aulendoff). 36 ΕΡ 2 598 503 / ΡΤ

Preferably, the composition according to the invention contains the compound according to the invention in an amount of 0.001 to 99% by weight, more preferably 0.1 to 90% by weight, more preferably 0.5 to 80% by weight. weight, more preferably 1.0 to 70% by weight, and especially 2.5 to 60% by weight, based on the total weight of the composition.

Preferably, the composition within the scope of the present invention is made for systemic, topical or local administration, preferably for oral administration.

A further object of the present invention relates to a pharmaceutical dosage form containing the pharmaceutical composition within the scope of the present invention.

In a preferred embodiment, the dosage form within the scope of the present invention is formulated so as to be administered twice daily, once daily, or for administration less than once daily, but preferably for administration more than once per day.

Preferably, it is a systemic administration, in particular orally.

In a preferred embodiment, the dosage form according to the present invention contains the compound according to the invention in such a small dose that it is not significantly effective in the treatment of acute pain. Preferably, this dose is in the range of 1.0 pg to 10 mg, based on the molecular weight of the free base.

Preferably the dose contains 0.001 mg ± 50%, 0.002 mg ± 50%, 0.003 mg ± 50%, 0.004 mg ± 50%, 0.005 mg ± 50%, 0.006 mg ± 50%, 0.007 mg ± 50%, 0.008 mg ± 50%, 0.009 mg ± 50%, 0.01 mg ± 50%, 0.02 mg ± 50%, 0.03 mg ± 50%, 0.04 mg ± 50%, 0.05 mg ± 50%, 0 , 0.08 mg ± 50%, 0.09 mg ± 50%, 0.1 mg ± 50%, 0.15 mg ± 50%, 0.2 mg ± 50% mg ± 50%, 0.25 mg ± 50%, 0.3 mg ± 50%, 0.35 mg ± 50%, 0.4 mg ± 50%, 0.45 mg ± 50%, 0.5 mg ± 0.75 mg ± 50%, 0.65 mg ± 50%, 0.7 mg ± 50%, 0.75 mg ± 50%, 0.8 mg ± 50% , 0.85 mg ± 50%, 0.9 mg ± 50%, 0.95 mg ± 50%, 1 mg ± 50%, 1.5 37 ± 2 598 503 / ΡΤ mg ± 50%, 2 mg ± 50 2.5 mg ± 50%, 3 mg ± 50%, 3.5 mg ± 50%, 4 mg ± 50%, 4.5 mg ± 50%, 5 mg ± 50%, 5.5 mg ± 50%, 6 mg ± 50%, 6.5 mg ± 50%, 7 mg ± 50%, 7.5 mg ± 50%, 8 mg ± 50%, 8.5 mg ± 50%, 9 mg ± 50% 5 mg ± 50%, or 10 mg ± 50%, based on the molecular weight of the free base.

More preferably, the dose contains 0.001 mg ± 25%, 0.002 mg ± 25%, 0.003 mg ± 25%, 0.004 mg ± 25%, 0.005 mg ± 25%, 0.006 mg ± 25%, 0.007 mg ± 25%, 0.008 mg ± 25%, 0.09 mg ± 25%, 0.01 mg ± 25%, 0.02 mg ± 25%, 0.04 mg ± 25%, 0.04 mg ± 25%, 0.05 mg ± 25% 0.06 mg ± 25%, 0.07 mg ± 25%, 0.08 mg ± 25%, 0.09 mg ± 25%, 0.1 mg ± 25%, 0.15 mg ± 25% 2 mg ± 25%, 0.25 mg ± 25%, 0.3 mg ± 25%, 0.35 mg ± 25%, 0.4 mg ± 25%, 0.45 mg ± 25%, 0.5 mg + 25%, 0.55 mg ± 25%, 0.6 mg ± 25%, 0.65 mg ± 25%, 0.7 mg ± 25%, 0.75 mg ± 25%, 0.8 mg ± 25% %, 0.85 mg ± 25%, 0.9 mg ± 25%, 0.95 mg ± 25%, 1 mg ± 25%, 1.5 mg ± 25%, 2 mg ± 25%, 2.5 mg , 25 mg, 25 mg, 25 mg, 25 mg, 25 mg, 25 mg, 25 mg, 25 mg, 25 mg, 25 mg, 25 mg, 6.5 mg ± 25%, 7 mg ± 25%, 7.5 mg ± 25%, 8 mg ± 25%, 8.5 mg ± 25%, 9 mg ± 25%, 9.5 mg ± 25% or 10 mg ± 25%, based on the molecular weight of the free base.

Still particularly preferably the dose is 0.001 mg, 0.002 mg, 0.003 mg, 0.004 mg, 0.005 mg, 0.006 mg, 0.007 mg, 0.008 mg, 0.009 mg, 0.01 mg, 0.02 mg mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg , 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg or 10 mg, based on the molecular weight of the free base.

In a preferred embodiment, the dosage form according to the invention contains the compound within the scope of the present invention in an amount of 10æg ± 90%, more preferably 10æg ± 75%, more preferably 10æg ± 50%, more preferably 10æg ± 25%, and particularly preferably 10æg ± 10%, based on the molecular weight of the free base.

In a further preferred embodiment, the dosage form according to the present invention comprises the compound of the invention with the invention in an amount of 100æg ± 90%, more preferably of 100æg ñ 75% more. preferably of 100æg ± 50%, more preferably still of 100æg ± 25% and more preferably of 100æg ± 10%, based on the molecular weight of the free base.

In another preferred embodiment, the dosage form according to the present invention contains the compound according to the invention in an amount of 250æg ± 90%, more preferably 250æg ± 75%, more preferably 250æg ± 50%, more preferably 250æg ± 25%, and in particular preferably 250æg ± 10%, based on the molecular weight of the free base.

In another preferred embodiment, the dosage form according to the invention contains the compound within the scope of the invention in an amount of 500æg ± 90%, more preferably 500æg ± 75%, more preferably 500æg ± 50æg %, more preferably 500 pg ± 25% and more preferably 500 pg + 10% based on the molecular weight of the free base.

In a further preferred embodiment, the dosage form according to the invention contains the compound within the scope of the present invention in an amount of 750æg ± 90%, more preferably 750æg ± 75%, more preferably 750æg ± 50% %, more preferably 750 pg ± 25% and in particular preferably 750 pg ± 10% based on the molecular weight of the free base.

In a further preferred embodiment, the dosage form according to the invention contains the compound within the scope of the present invention in an amount of 1000 pg ± 90%, more preferably 1000 pg ± 75%, more preferably 1000 pg ± 50%, and more preferably 1000æg ± 25% and in particular 1000æg ± 10% based on the molecular weight of the free base. The dosage form according to the invention may for example be administered as a liquid dosage form in the form of injection solutions, drops or juices or a semi-solid dosage form in the form of granules, tablets, pellets, patches, capsules, patches or sprays 39 ΕΡ 2 598 503 / ΡΤ dressings or aerosols. The choice of additives and excipients, etc., as well as their amounts will depend on the dosage form administered and how it is to be administered, whether orally, perorally, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally , buccal, rectal or topically applied, for example on the skin, mucous membranes or eyes.

Dosage forms for oral administration are suitable in the form of tablets, dragees, capsules, granules, drops, juices and syrups, for the parenteral route we have topical and inhalation solutions, suspensions, easily reconstituted dry preparations and sprays. The compounds within the scope of the present invention are suitable for percutaneous administration when in the form of a depot, in the dissolved form or in the form of a patch, optionally with the addition of skin penetration facilitating means.

Dosage forms for oral or percutaneous administration may allow the delayed release of the compounds within the scope of the present invention. The compounds according to the invention may be used in long-term depot forms for parenteral applications, such as implants or implanted pumps. In principle, the dosage forms according to the invention may contain other active ingredients known to those skilled in the art which may be added thereto.

In a preferred embodiment, the compounds within the scope of the present invention are released immediately from the dosage form (immediate release: IR), that is preferably under in vitro preferred conditions according to Ph. Eur. after 20 minutes at least 80% of the active ingredient initially contained is released.

The compounds within the scope of the present invention have been found to be surprisingly characterized as having a remarkably long half-life (11/2) or duration of pharmacodynamic action, so that relatively less administration or use is in 40 ΕΡ 2 598 503 / ΡΤ sufficient to achieve comparatively longer pharmacological activity and therefore pain relief.

Delayed-release dosage forms of the compounds within the scope of the present invention are not mandatory, even if with immediate release (IR) a long-lasting effect is obtained as a consequence of the longer half-life. Due to the IR property of such dosage forms, these then have the additional advantage that in longer and longer lasting efficacy however we have a rapid absorption of the active ingredient (rapid onset, rapid onset) and thus a rapid onset of pharmacological activity can be obtained soon after the first administration. Thus, the properties of IR dosage forms are combined with properties of forms of PR administration (PR: prolonged release: sustained release, delayed release).

In a preferred embodiment the dosage form according to the invention is an immediate release (IR) dosage form, which is a compound within the scope of the present invention, preferably of the general formula (V) or (VI), as a free base or a physiologically acceptable salt, preferably containing a hydrochloride, citrate or hemicitrate and is made up for a take up no more than once per day, preferably exactly once only per day, preferably for administration by oral route. In this context, &quot; immediate release of the active ingredient &quot; means that under conditions in vitro and preferably according to the European Pharmacopoeia, after 20 minutes at least 80% of the active ingredient originally contained is released. The amount to be administered to the patient of the compounds within the scope of the invention will vary depending upon the weight of the patient, the mode of administration, the indication and the severity of the disease. Normally and generally between 0.00005 and 50 mg / kg, preferably between 0.001 and 0.5 mg / kg, preferably still between 1 and 10 pg / kg of at least one compound within the scope of the present invention is administered. 41 ΕΡ 2 598 503 / ΡΤ

For all prior embodiments of the dosage forms according to the invention, it is particularly preferred that the dosage form in addition to at least one compound within the present invention also contains another active ingredient. The 0RL1 receptor and the receptor-opioid are associated, in particular, with the occurrence of pain. Accordingly the compounds within the scope of the present invention for the manufacture of a medicament for the treatment of chronic pain may be used, preferably for neuropathic pain, more preferably for mononeuropathic / neuralgic pain or polyneuropathic pain, even more preferably for post-herpetic neuralgic pain or in diabetic polyneuropathy.

The following examples serve to illustrate the present invention but are not to be construed as limiting thereof:

In the following stereochemistry nomenclature of the compounds used as examples, the term &quot; (E) &quot; refers to the substitution of a double bond, for example, of a cinnamic acid derivative, and the term &quot; cis &quot; or &quot; trans &quot; refers to substitution on the cyclohexyl ring. Synthesis of the constituent blocks indole (H)

Constituent block H-1: 2- (1H-indol-3-yl) ethanamine (H-1)

For the time being the synthesis is commercially available from Aldrich.

H-2: 2- (5-Fluoro-1H-indole-3-yl) ethanamine (H-2)

At the moment the synthesis is commercially available from Fluorochem. 42 ΕΡ 2 598 503 / ΡΤ

Synthesis of the constituent blocks of ketone (E)

Constituent block E-1:

To a solution of 1.82 M of phenylmagnesium chloride in THF (109 ml, 0.198 g) in dichloromethane (10 ml) mol) is added under argon and ice-cooled over a period of 15 min, aminonitrile B1 (21 g, 0.1 mol) dissolved in THF (210 ml) is stirred at room temperature for 16 h. To treat the reaction mixture, a saturated ammonium chloride solution is added under ice-cooling (150 ml) and extracted with diethyl ether (3 x 100 ml). The organic phase is then stirred and concentrated with water (100 ml) and saturated NaCl solution (100 ml). A yellow oil (25.2 g) is then obtained. The crude product is then dissolved in ethyl methyl ketone (280 ml) and under ice cooling conditions CISiMe 3 (18.8 ml, 0.15 mol) is added. After a reaction time of 6 h, the hydrochloride D-1 is then isolated as a white solid in 35% yield (10.5 g). 4-dimethylamino-4-phenylcyclohexanone (E-1) The hydrochloride D-1 (10.5 g, 35.2 mmol) is dissolved in 7.5 N hydrochloric acid (36 ml) and stirred at room temperature for 96 h. Upon completion of the hydrolysis, the reaction mixture is extracted with diethyl ether (2 x 50 mL). The aqueous phase is made alkaline with 5N sodium hydroxide solution under ice cooling, extracted and concentrated (50 ml) three times with dichloromethane. Ketone 6 may thus be isolated as a yellow solid with a melting point of 104-108 ° C and in 97% yield (7.4 g). 43 ΕΡ 2 598 503 / ΡΤ

Constituent block Ε-2:

Variant 1:

[8- (3-fluorophenyl) -1,4-dioxaspiro [4,5] dec-8-yl] -dimethylamine hydrochloride (D-2) To a solution of the aminonitrile B1 (19.8 g, 94 mmol) in A solution of 3-fluorophenylmagnesium bromide in THF (3, 750 ml, 375 mmol) is added under argon and ice-cooling over a period of 15 minutes, and then all stirred for 16h at room temperature. To treat the reaction mixture, a solution of saturated ammonium chloride (150 ml) and water (60 ml) under ice-cooling conditions is added and all is extracted with diethyl ether (3 x 100 ml). The organic phase is then stirred and concentrated with water (50 ml) and saturated NaCl solution (50 ml). There is then obtained a brown oil (26.5 g), which in addition to the phenyl compound 4, still contains the ketal 2. The crude product is then dissolved in ethyl methyl ketone (156 ml) and under ice-cooling it is added CISiMe 3 (17.8 mL, 141 mmol). After a reaction time of 6h, the hydrochloride D-2 is isolated as a white solid with a melting point of 275-278øC and in a yield of 55% (16.3 g).

Variant 2:

To a solution of 1-bromo-3-fluorobenzene (5.00 g, 0.8 mmol) in dichloromethane 28.6 mmol) in abs. (15 ml) is added a suspension of magnesium (694 mg, 28.6 mmol) in abs. Ether. (10 ml) dropwise in such a manner as to allow the ether to boil. Upon completion of the addition, the mixture is stirred for 10 min at room temperature, and the magnesium is then completely dissolved. The reaction solution is then cooled in an ice bath and at 10 ° C the aminonitrile B-1 (3.00 g, 14.3 mmol) in abs. THF is added dropwise. (30 ml). The solution is then stirred at room temperature overnight, and the reaction under ice-cooling undergoes addition of a 20% solution of NH 4 Cl (20 ml) and water (30 ml) and then extraction with ether (3x50ml). The organic phase is then washed with water (50 ml) and then with a saturated NaCl solution (50 ml), dried over Na 2 SO 4 and concentrated in vacuo. The crude product is dissolved in ethyl methyl ketone (25 mL), CISiMe 3 (3.2 mL, 25 mmol) is added under ice-cooling and stirred at room temperature for 5 h. The resulting precipitate is then filtered and concentrated in vacuo.

Yield of D-2: 2.8 g (62%) 1 H-NMR (DMSO-d6): 1.91 (8H, m); 2.54 (6H, s); 3.91 (4H, d); 7.37 (1H, m); 7.61 (3H, m).

The hydrochloride D-2 (7.2 g, 22.75 mmol) is dissolved in water (9.6 ml.) In dichloromethane ), concentrated hydrochloric acid (14 ml, 455 mmol) is added and allowed to stir for 4 days at room temperature. Upon completion of the hydrolysis, the reaction mixture is extracted with diethyl ether (2 x 50 mL), the aqueous phase is basified with 5N sodium hydroxide solution under ice-cooling conditions, under which conditions the precipitation of product. Ketone E-2 is isolated as a yellow solid with a melting point of 83-88 ° C and a 50% yield (6.05 g).

The hydrochloride D-2 (2.80 g, 8.86 mmol) is dissolved in water (3.7 mL) ) and has the addition of concentrated hydrochloric acid (5.5 ml), then stirred at room temperature for 4 days. After completion of the hydrolysis, the reaction mixture is extracted with ether (2 x 10 ml), the aqueous solution is cooled to ice with 5N sodium hydroxide solution under ice-cooling, the reaction mixture is then extracted with dichloromethane ( 3x50 ml), the organic phase then dried over sodium sulfate and concentrated in vacuo. The crude product is then purified by flash chromatography with CHCl 3 / MeOH (20: 1).

E-2 yield: 676 mg (32%), colorless solid. Melting point: 62-67Â ° C 45Â ° C 598 503 / ¹H-NMR (DMSO-d6): 2.02 (6H, s); 2.12 (5H, m); 2.45 (3H, m); 7.24 (3H, m); 7.43 (1H, m).

E-3 constituent block:

[8- (4-fluorophenyl) -1,4-dioxaspiro [4.5] dec-8-yl] dimethylamine hydrochloride (D-3) To a solution of aminonitrile B1 (10.5 g, 50 mmol) in THF (150 ml) under argon and ice-cooling is added a 1M solution of 4-fluorophenyl magnesium bromide in THF (3.125 ml, 125 mmol) over a period of 15 minutes and then stirred at room temperature for 16 h. To treat the reaction mixture, a solution of saturated ammonium chloride (37 ml) and water (50 ml) is added under ice-cooling and the product is extracted with diethyl ether (3 x 100 ml). The organic phase is shaken and concentrated with water (50 ml) and saturated NaCl solution (50 ml). A brown residual oil (12.55 g) is obtained which, in addition to the phenyl C-3 compound, further contains ketal B-1. The crude product is then dissolved in ethyl methyl ketone (75 ml) and added with ice-cooling CISiMe 3 (9.5 ml, 75 mmol). After a reaction time of 6h, the hydrochloride D-3 is isolated as a white solid in 47% yield (7.48g). 4-dimethylamino-4- (4-fluorophenyl) cyclohexanone (E-3) The hydrochloride D-3 (7.2 g, 22.75 mmol) is dissolved in water (9.6 ml), concentrated hydrochloric acid (14 mL, 455 mmol) and stirred for 4 days at room temperature. After completion of the hydrolysis, the reaction mixture is extracted with diethyl ether (2 x 50 mL), the aqueous phase is made alkaline with 5N sodium hydroxide solution and under ice-cooling under extraction and concentration with dichloromethane (3 x 50 mL ). Ketone E-3 is isolated as a yellow solid with a melting point of 128-133 ° C and 76% yield (4.05 g). 46 ΕΡ 2 598 503 / ΡΤ

Constituent block Ε-4:

(8-thiophen-2-yl-1,4-dioxaspiro [4.5] dec-8-yl) amine (D-4) O-thiophene of iodine (1.22.9 g, mmol) is dissolved in THF (80 mL) under argon and a 2M solution of isopropyl magnesium chloride in THF (2.35.7 mL, 72 mmol) is poured at 0 ° C. After a reaction time of 1 h at 3-5øC, aminonitrile B-1 (10 g, 47.6 mmol) is dissolved in tetrahydrofuran (20 ml) and stirred for 20 h at room temperature. Treatment of the mixture proceeds by the addition of a saturated solution of NH4 Cl (85 ml) and extraction with diethyl ether (3x100 ml). The organic phase is then stirred and concentrated with water (50 ml) and saturated NaCl solution (50 ml). A dark brown oil (21.3 g) may then be obtained which, in addition to the desired ketal, also also contains aminonitrile B-1 and 2-thiophene of iodine. The crude product is then dissolved in ethyl methyl ketone (140 ml) and treated with CISiMe 3 (9.1 ml, 71.4 mmol). After a reaction time of 6 h, the hydrochloride D-4 is isolated as a white crystalline compound in 60% yield (8.74 g). 4-dimethylamino-4-thiophen-2-yl-cyclohexanone (E-4) The hydrochloride D-4 (8.68 g, 28.6 mmol) is dissolved in 7.5 N hydrochloric acid (29 ml) and stirred for 48 h at room temperature. Upon completion of the hydrolysis, the reaction mixture is extracted with diethyl ether (2 x 50 mL). The aqueous phase is then basified with 5N sodium hydroxide solution under ice-cooling and then extracted and concentrated with dichloromethane (3x50 ml). The ketone E-4 is then obtained as a yellow solid with a melting point of 108-110øC and in a yield of 89% (5.66 g).

E-5 constituent: N-dimethyl-8- (thiophen-3-yl) -1,4-dioxaspiro [4,5] decan-8-amine (E-5) 3-thiophene , 5 g, 23.8 mmol) is dissolved under argon in THF (18 mL) and over a period of 8 min 47 Å Å 2 598 503 / ΡΤ is added at 0øC a 2M solution of magnesium chloride of isopropyl (2, 7.8 mL, 15.5 mmol) in THF. After a reaction time of 1h at 3-5øC, the aminonitrile B-1 (2.16 g, 10.3 mmol) dissolved in tetrahydrofuran (20 ml) is added. Then all is stirred at room temperature for 20 hours. Treatment of the mixture is then effected by the addition of saturated NH 4 Cl (20 ml) and extraction with diethyl ether (3 x 50 ml). The organic phase is then stirred and concentrated with water (20 ml) and saturated NaCl solution (20 ml). There is thus obtained a light brown oil (3.95 g). The crude product is then dissolved in ethyl methyl ketone (40 mL) and treated with CISiMe 3 (1.95 mL, 15.5 mmol). After a reaction time of 3 hours, the desired hydrochloride is isolated as a white crystalline compound, in 60% yield (1.86 g) and a melting point of 250-251 ° C. 4- (dimethylamino) -4- (thiophen-3-yl) cyclohexanone (E-5) The hydrochloride D-5 (1.8 g, 5.9 mmol) is dissolved in 7.5 N hydrochloric acid ml) and stirred for 48 h at room temperature. After completion of the hydrolysis, the reaction mixture is extracted with diethyl ether (2 x 30 mL) under ice-cooling, the aqueous phase is made alkaline with 5N sodium hydroxide solution and extracted and concentrated with dichloromethane (3 x 30 mL) . Ketone E-5 is then isolated and obtained as a yellow solid having a melting point of 147-150 ° C and a yield of 98% (1.27 g). Synthesis of constitutive blocks of spiroamine (AMNC1S / AMNtrans)

Comparative Example AMN-1C2S: 2 ', 3', 4 ', 9' -tetrahydro-N, N-dimethyl-4- (phenyl) -spiro [cyclohexane-1,1 '(1'H) - pyrido [3,4-b] indole] -4-amine (cis diastereomer)

48 ΕΡ 2 598 503 / ΡΤ

Note: According to this provision, the cis product AMN-1C2S is obtained mainly. The trans AMN-tetraamine product is obtained only as a byproduct or contamination. The E-1 ketone (3.26 g, 15 mmol) and tryptamine H-1 (2.4 g, 15 mmol) are dissolved in the absence of oxygen in dry MeOH (100 mL). To this mixture is added sodium sulfate (3 g). After a reaction time of 17 h, the solvent is distilled off on a rotary evaporator and the residue is taken up in 1,2-dichloroethane (100 ml). The reaction mixture is then treated with trifluoroacetic acid (15 ml) and stirred at room temperature for 1 h. The course of the reaction is monitored by TLC. For subsequent treatment, to the mixture is added H 2 O (40 mL) and this is adjusted with NaOH (5 mol / l) to pH 11. A white solid precipitate is obtained, which is filtered under vacuum conditions on a frit. The solid is then washed with H2O (3 x 5 mL) and dried. The product obtained is then the product cis-AMN-1c: which is a white solid, m.p. 214-218Â ° C in 4 g (74%) yield. The mother liquor (aqueous phase) is extracted with 1,2-dichloroethane (3x25 ml). The organic phase is dried with Na2 SO4 &gt; 4 and concentrated. The brown solid residue was recrystallized from solution with MeOH (10 mL) to afford a mixture of cis-AMN-1c: 1 and trans-AMN-1rates (1: 1) spiroamines. The mixture is obtained as a white solid in a yield of 940 mg (17%). Δ NMR (600 MHz, DMSO-d6): 1.61 (m, 2H) 1.63 (m, 2H) 1.92 (s, 6H) 2.12 (m, 2H) 2.39 (m, 2H ) 2.53 (t, J = 5.36Hz, 2H) 2.99 (t, J = 5.35Hz, 2H) 6.86 (m, 1H) 6.91 (m, 1H) 7.16 (d, J = 7.52 Hz, 1 H) 7.31 (m, 1 H) 7.43 (m, 4H) 10.21 (s, 1H )

Comparative Example AMN-2C1S: 2 ', 3', 4 ', 9' -tetrahydro-N, N-dimethyl-4- (3-fluorophenyl) -spiro [cyclohexane-1,1 ' ) pyrido [3,4-b] indole] -4-amine (cis diastereomer) 49 ΕΡ 2 598 503 / ΡΤ

The ketone E-2 (4.71 g, 20 mmol) and tryptamine H-1 (3.2 g, 20 mmol) are dissolved under argon in dry MeOH (200 mL). After a reaction time of 24 hours, the MeOH is removed by distillation and the yellow oily residue obtained is placed in a suspension with 1,2-dichloroethane (200 ml). The reaction mixture is then treated with trifluoroacetic acid (20 ml) and stirred at room temperature for 2 h. The course of the reaction is monitored by TLC. For the course of the procedure the mixture was diluted with H 2 O (100 mL) and adjusted to pH 11 with a NaOH solution (5 mol / l). After the addition of ethyl acetate (50 ml) there is obtained under stirring a white solid which is filtered under vacuum on a frit. The solid is washed with H2O (3x25 mL) and then dried. This is the case for the diastereomer cis-AMN-2 Cl, which is obtained as a white solid having a melting point of 220-225 ° C in a yield of 5.5 g (73%). 2H) 1.62 (m, (t, J = 5.56 6.92 (m, 1H) 1H) 7.25 (d, (m, 1H) 10.26 2H) 1.93 (s, 1 H NMR (600 MHz, DMSO-d 6): 1.61 (m, 6H), 2.11 (m, 2H), 2.38 (m, 2H), 2.53 (t, J = 5.56Hz, 2H) 6.87 (m, 1H) 7.17 (d, 20 (m, 1 H) 7.28 (d, J = 7.47 Hz, 1 H) 7.47

Comparative Example AMN-2S): 2 ', 3', 4 ', 9' -tetrahydro-N, N-dimethyl-4- (3-fluorophenyl) -spiro [cyclohexane-1,1 ' ) -pyrido [3,4-b] indole] -4-amine (trans diastereomer)

(2.03 g, 12.7 mmol) and ketone E-2 (3.0 g, 12.7 mmol) are dissolved in abs. Methanol. (130 ml) and stirred at room temperature for 16 h under an argon atmosphere. The reaction mixture is then concentrated. The residue is then dissolved in abs. 1,2-dichloroethane. (130 ml), trifluoroacetic acid (12.7 ml) is added rapidly and the whole stirred for 2 h at room temperature. Under ice-cooling water (120 ml) and 5N sodium hydroxide solution (40 ml) are added and the whole is stirred again for 1 h. In this way, the resultant colorless solid is collected and separated by filtration and washed with 1,2-dichloroethane (30 ml) and water (4 x 25 ml). The cis spiroamine AMN-2C1S is then obtained in a yield of 77% (3.7 g) with traces of trans-AMN-2 trans-spiroamine. The phases of the filtrate are then separated. The organic phase is dried over sodium sulfate, concentrated, treated with methanol (3 ml) and stirred for 1 h at room temperature. A white solid precipitates which is then separated by filtration and washed with methanol (4 x 3 ml). The trans-AMN-2tra / 3S spiroamine is then obtained in 5% yield (250 mg) with traces of cis-AMN-2c: cis spiroamine. After chromatographic purification [silica gel 60 (20 g); Methanol (200 ml)] is then obtained the trans spiroamine AMN-2rates (170 mg) having a melting point of 296-299 ° C. Δ NMR (600 MHz, DMSO-d6): 1.55 (m, 2H) 1.62 (m, 2H) 1.88 (s, 6H) 2.26 (m, 2H) 2.43 (m, 2H ) 2.55 (t, J = 5.49 Hz, 2 H) 2.96 (t, J = 5.25 Hz, 2 H) 6.91 (m, 1 H) 6.99 (m, 1 H) 7.08 (m, 1 H) 7.14 (m, 1 H) 7.20 (d, J = 7.64 Hz, 1 H) 7.32 (m, 2 H) 7.40 (m, 1 H) 10.63 (s, 1H)

Comparative Example AMN-3C2S: 6'-fluoro-2 ', 3', 4 ', 9' -tetrahydro-N, N-dimethyl-4- (3-fluoro-phenyl) -spiro [cyclohexane-1 , 1 '(1'H) -pyrido [3,4-b] indole] -4-amine (cis diastereomer)

(9.6 g, 41.2 mmol) and fluor tryptamine H-2 (7.3 g, 41.2 mmol) are dissolved in ethanol (200 ml) and all is heated at reflux for 12 hours. Then the ethanol is removed by distillation and the crude product is suspended in 1,2-dichloroethane (100 ml). The reaction mixture is then treated with trifluoroacetic acid (90 ml) and stirred at room temperature for 12 h. The course of the reaction is monitored by TLC. For further treatment, the mixture is adjusted to the alkaline pH with 500 ml of 1N NaOH solution and at a temperature 0 ° C and then extracted with ethyl acetate 3x500 ml. The combined organic phases are dried over magnesium sulfate, and concentrated under reduced pressure. After the addition of methanol (100 ml), and while stirring, a white solid precipitates, which is vacuum filtered on a frit. The solid is washed with methanol (2 x 25 mL) and then dried. This is the case for the cis-diastereomers AMN-3 Cl, which is obtained as a white solid in a yield of 3.6 g (22%). Δ NMR (DMSO-d 6, 400 MHz): 10.39 (s, 1H), 7.44-7.49 (m, 1H), 7.11-7.24 (m, 4H), 7.00- 7.04 (m, 1H), 6.72-6.78 (m, 1H), 2.95-2.98 (t, 2H), 2.48-2.50 (m, 1H) 36-2.39 (d, 2H), 1.98-2.11 (m, 2H), 1.91 (s, 6H), 1.51-1.67 (m, 5H) MS m / z ( M + 1): 396.4; Purity (HPLC): 95.03%

Comparative Example AMN-4 Cl5: 6'-fluoro-2 ', 3', 4 ', 9' -tetrahydro-N, N-dimethyl-4- (phenyl) -spiro [cyclohexane-1,1 ' 1 'H) pyrido [3,4-b] indole] -4-amine (cis diastereomer)

Ketone E-1 (8.4 g, 47 mmol) and fluor tryptamine H-2 (10.2 g, 47 mmol) are dissolved in ethanol (200 ml) and the whole is heated at reflux for 12 hours. Then the ethanol is removed by distillation and the crude product is kept in suspension in 1,2-dichloroethane (120 ml). The reaction mixture is then treated with trifluoroacetic acid (100 ml) and stirred at room temperature for 12 h. The course of the reaction is monitored by TLC. For the following treatment, the mixture is passed to alkaline pH with 1 N NaOH solution at a temperature of 0 ° C and then extracted three times with 500 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure. After the addition of methanol (100 ml), during the stirring process, a white solid precipitates out which is filtered under vacuum on a frit. The solid is then washed with methanol (2 x 25 mL) and then dried. This is a cis-diastereomer AMN-4CS, which is obtained as a white solid in 4 g (28%) yield. Δ NMR (DMSO-d6, 400 MHz): 10.36 (s, 1H), 7.45-7.42 (t, 4H), 7.32-7.29 (m, 1H), 7.14- 7.10 (m, 1H), 7.03-7.00 (m, 1H), 6.76-6.71 (m, 1H), 2.99-2.96 (t, 2H) 40-2.37 (d, 2H), 2.13-2.04 (m, 2H), 1.91 (s, 6H), 1.88 (s, 1H), 1.65-1.54 ( m, 4H), 1.23 (s, 1H).

Comparative example AMN-5C2S: 2 ', 3', 4 ', 9' -tetrahydro-N, N-dimethyl-4- (4-fluorophenyl) -spiro [cyclohexane-1,1 ' ) -pyrido [3,4-b] indole] -4-amine (cis diastereomer)

E-3 ketone (2800 mg, 11.90 mmol) and tryptamine (H-1, 1910 mg, 11.90 mmol) are dissolved under argon in dry methanol (119 mL) and the whole is stirred for 18 h. The methanol is then removed by distillation in vacuo and the residue is kept in suspension in 1,2-dichloroethane (119 ml). The reaction mixture is then treated with trifluoroacetic acid (11.9 ml) and stirred at room temperature for 2 h. Then, the reaction mixture is diluted with 1,2-dichloroethane (119 ml) and with ice-cooling its pH is adjusted to 53 ÅΡ 2 598 503 / ρ ρ 11 with 1N sodium hydroxide solution. A pale precipitate is formed. The mixture is stirred overnight at room temperature. The precipitate is filtered, washed with water and dried under vacuum. The cis-diastereomer AMN-5CiS (m.p. 249-250Â ° C, sometimes even 225-230Â ° C) is isolated and obtained in 80% yield (3610mg, 9.56mmol). The phases are then separated. The organic phase is dried over sodium sulfate, filtered and the volatiles removed in vacuo. The light residue (trans diastereoisomer AMN-5-trails) is collected in methanol (5 ml) and stirred for 48 h. The precipitate is then filtered and dried under vacuum. The trans-AMN-5 trans diastereoisomer (268-271 ° C) is finally isolated in 6% yield (279 mg, 0.74 mmol). 13 C (1H) -MRN (101 MHz, DMSO-D 6) ppm: 22.8 (1 C), 27.3 (2 C), 32.6 (2 C), 37.8 (2 C) 6 (1 C), 51.2 (1 C), 60.5 (1 C), 106.7 (1 C), 110.8 (1 C), 114.2 (2 C, d, J = 21 117.9 (1 C), 117.9 (1 C), 120.0 (1 C), 126.9 (1 C), 129.7 (2 C, d, J = 8 Hz), 132.8 (1 C, d, J = 3 Hz), 135.4 (1 C), 141.4 (1 C), 160.7 (1 C, d, J = 242 Hz)

Synthesis of examples of cis spiroamide (DDCis)

Example AMD-1g:

(E) -2 ', 3', 4 ', 9' -tetrahydro-N, N-dimethyl-4-phenyl-2 '- (2-phenylvinyl) carbonyl-spiro [cyclohexane- 1 '(1'H) -pyrido [3,4-b] indole] -4-amine (1: 1) (cis diastereomer)

The AMN-1C 2 S is dissolved in THF (8 mL). Cinnamoyl chloride or cinnamic acid (254 mg, 54 Å, 598 503 / ΡΤ 1.53 mmol) and diisopropylethylamine (216 mg, 1.67 mmol) are then added and all stirred for 2 days at room temperature. After the completion of the reaction, the solid is removed by filtration and the filtrate is treated with saturated Na2CO3 solution. The aqueous phase is extracted three times with 10 ml of ethyl acetate. Finally the organic phase is dried over MgSO4 and concentrated on a rotary evaporator. The crude product is purified by column chromatography [silica gel 60; DCM / methanol (19: 1, 570 mL)]. The product is then obtained in a yield of 174 mg (26%). For the preparation of the methanesulfonate the spiroamide obtained above (174 mg, 0.355 mmol) is suspended in DCM (6 mL) and at ambient temperature undergoes the addition of methanesulfonic acid (23.7 μ, 0.355 mmol). Then acetone (0.8 ml) and diethyl ether are added so that the apparent initial turbidity is easily removed by stirring. Stirring is continued for a further 30 min and the resulting solid is then suction filtered with exclusion of air, washed with diethyl ether and dried under vacuum with an oil pump at 50 ° C for 3 h. The AMD-1CiS product is obtained in a yield of 159 mg (76%). Δ NMR (600 MHz, DMSO-d6) Î'1.65 (t, J = 13, 22 Hz, 2H) 2.20 (t, J = 12.8, 4 Hz, 2H) d, J = 4.53, H: z, 9 H), &gt; (br s, 2H) 6.92 (t, J = 7.55, H: z, 1H) 6.99 (t, J = 7.55 Hz, (D, J = 7.5 Hz, 1H), 7.36-7.51 (m, 5H), 7.56-7.75 (m, 69 (m, 3H), 7.74 (d, J = 7.55 Hz, 2H), 8.22 (d, J = 7.55 Hz, 2H), 9.62 (br. S, 1H).

Comparative examples AMD-2C1S 2 ', 3', 4 ', 9' -tetrahydro-N, N-dimethyl-4- (3-fluoro-phenyl) -2'-chlorobenzyl) -carbonyl-spiro [cyclohexane -1,1 '- (1'H) -pyrido [3,4-b] indole] -4-amine (cis diastereomer) 55 ΕΡ 2 598 503 / ΡΤ

Spiroamine (AMN-2C2S, 396 mg, 1.05 mmol) is suspended in DCM (15 mL) in a vessel suitable for microwave heating conditions, and thereafter 2- (4-chlorophenyl) acetyl chloride (397 mg, 2.1 mmol) and diisopropylethylamine (269 mg, 2.1 mmol). The reaction mixture is then kept under microwave irradiation at 120 ° C for 10 min. (Initiator Eight, Signature Biotage). After the completion of the reaction (TLC monitoring), the reaction mixture is first filtered, added and washed with diethyl ether (15 ml) and further filtered. A saturated Na 2 CO 3 solution (8 mL) is added. After separating the phases, the aqueous phase is washed again with DCM. The combined organic phases are then dried over MgSO4 and concentrated on a rotary evaporator. The crude product is purified by column chromatography [silica gel 60; DCM / methanol (19: 1)]. The AMD-2c: is then obtained in 91 mg (16%) yield. Δ NMR (600 MHz, DMSO-d 6) d ppm 1.55 (t, J = 13.60 Hz, 2 H) 1.79 (t, J = 12.84 Hz, 2 H) 1.92 (br. S, 6H) 2.60-2.70 (m, 2H) 2.73-2.87 (m, 2H) 3.17 (d, J = 5.29 Hz, 2H) 3.89-4.01 (m , 4H) 6.90 (t, J = 7.55 Hz, 1 H) 6.97 (t, J = 7.55 Hz, 1 H) 7.08-7.16 (m, 1 H) 7.18 (d, J = 8.31 Hz, 1 H) 7.21-7.30 (m, 3 H) 7.34 (q, J = 8.31 Hz, 4 H) 7.46 (q, J = 7.30 Hz, 1H) 10.53 (s, 1H)

Comparative examples AMD-3c: is 2 ', 3', 4 ', 9' -tetrahydro-N, N-dimethyl-4- (3-fluorophenyl) -2 '- (benzothiophene-2-yl) carbonyl spiro [cyclohexane-1,1 '(1'H) -pyrido [3,4-b] indole] -4-amine hydrochloride (cis diastereomer) 56 ΕΡ 2 598 503 / ΡΤ

The spiroamine AMN-2CiS (264 mg, 0.7 mmol) is suspended in DCM (7 mL) in a vessel suitable for microwave maintenance and is treated with benzo [b] thiophene-2-carbonyl chloride (239 mg mg, 1.21 mmol) and diisopropylethylamine (180 mg, 1.4 mmol). The reaction mixture is then subjected to microwave radiation at 100 ° C for 10 min. (Initiator Eight, Signature Biotage). Upon completion of the reaction (TLC monitoring), the reaction mixture is diluted with DCM (15 mL) and filtered. The mother liquor is treated with saturated Na 2 CO 4 solution (8 ml). After the phases are separated, the aqueous phase is washed twice with DCM. The combined organic phases are dried over MgSO4 and concentrated on a rotary evaporator. The crude product is purified by column chromatography [silica gel 60; DCM / methanol (19: 1)]. The AMD-3CiS product is then obtained in a yield of 125 mg (33%). NMR (600 MHz, DMSO-d6) ppm 1.63-1.79 (m, 2H) 1.83-1.93 (m, 2H) 1.95 (s, 6H) 2.60 (d, J = = 13.60 Hz, 2H) 2.65 (t, J = 5.67 Hz, 2H) 2.78-2.94 (m, 2H) 4.08-4.22 (m, 2H) 6.92 (t, J = 7.55 Hz, 1 H) 6.99 (t, J = 7.55 Hz, 1 H) 7.16 (t, 8.31 Hz, 1 H) 7.26-7.36 (m, 3H) 7.44-7.54 (m, 3H) 7.95 (s, 1H) 8.03 (d, J = 7.55 Hz, 1 H) 8.07 (d, J = 8.31

1H), 10.66 (s, 1H)

Comparative Examples AMD-4C2S

2 ', 3', 4 ', 9' -tetrahydro-N, N-dimethyl-4- (3-fluorophenyl) -2 '- (4-fluorobenzyl) carbonylspiro [ 1 '(1'H) -pyrido [3,4-b] indole] -4-amine hydrochloride (cis diastereomer) 57 ΕΡ 2 598 503 / ΡΤ

Spiroamine (AMN-2CS, 600 mg, 1.59 mmol) is suspended in DCM (15 mL) in a microwave-safe vessel and treated with 2- (4-fluorophenyl) acetyl chloride (548 mg, 3.18 mmol) and diisopropylethylamine (408 mg, 3.18 mmol). The reaction mixture is then kept under microwave irradiation at 130 ° C for 10 min. (Initiator Eight, Signature Biotage). After the completion of the reaction (TLC monitoring), the reaction mixture is filtered, the mother liquor is diluted with DCM (45 ml) and treated with saturated Na 2 CO 4 solution (3 ml, 25 ml). After separating the phases, the organic phase is washed again with a saturated solution of Na2 CO &gt; 3. The organic phase is then dried over MgSO 4 and concentrated on a rotary evaporator. The crude product is purified by column chromatography [silica gel 60; DCM / methanol (4: 1)]. The product is then obtained in a yield of 150 mg (18%). For the preparation of the methanesulfonate the spiroamide (150 mg, 0.29 mmol) is dissolved in DCM (1 mL) and treated at room temperature with methanesulfonic acid (18.9 μ, 0.29 mmol). The mixture is diluted with diethyl ether to obtain and maintain the mixture in the state of stirring. The solid is filtered by suction excluding air, washed with diethyl ether and dried at 50 ° C in an oil vacuum pump. The AMD-4C2S product is obtained in a yield of 148 mg (83%). NMR (600 MHz, DMSO-d6) d ppm 1.58 (t, J = 12.84 Hz, 2H) 2.16 (t, J = 12.09 Hz, 2H) 2.31 (s, 3H) 2 , 53-2.58 (m, 6H) 2.58-2.68 (m, 2H) 2.83-3.03 (m, 4H) 3.98 (s, 2H) 3.99-4.06 (t, J = 8.31 Hz, 1 H), 6.92 (t, J = 7.18 Hz, 1 H) 7.18 (d, J = 8.31 Hz, 1 H) 7.29 (d, J = 7.55 Hz, 1 H) 7.36 (t, J = 6.42 Hz, 2 H) , J = 7.93

1H), 7.58-7.75 (m, 3H), 9.65 (br. S, 1H) 58 ΕΡ 2 598 503 / ΡΤ

Example AMD-5C2S (Ε) -2 ', 3', 4 ', 9' -tetrahydro-N, N-dimethyl-4- (3-fluorophenyl) -2 '- (2-phenylvinyl) carbonyl-spiro [ cyclohexane-1,1 '(1'H) -pyrido [3,4-b] indole] -4-amine (cis diastereomer)

Spiroamine (AMN-2C2S, 378 mg, 1.0 mmol) is dissolved in anhydrous aprotic solvent (6 mL), is treated with cinnamic acid chloride (183 mg, 1.1 mmol) and diisopropylethylamine (155 mg, 2 mmol) and stirred overnight at room temperature. Upon completion of the reaction (TLC monitoring), the solvent is removed, the residue is subjected to aqueous treatment and extracted with halogenated solvents. The combined organic phases are dried over Na2SO4 and concentrated. The crude product is purified by column chromatography. During the purification process, a solid precipitate is generated which is filtered and then dried. The product is obtained in 220 mg (43%) yield. NMR (600 MHz, DMSO-d 6) d ppm 1.63 (t, J = 13.60 Hz, 2 H) 1.84 (t, J = 13.22 Hz, 2 H) 1.91 (s, 6H) 2 (D, J = 5.67 Hz, 2 H) 2.82-3.02 (m, 2 H) 3.17 (d, J = 5.29 Hz, , 2H) 4.00-4.22 (m, 2H) 6.90 (t, J = 7.18 Hz, 1 H) 6.97 (t, J = 7.55 Hz, 1 H) 7.11-7 1H), 7.20 (d, J = 8.31 Hz, 1 H) 7.23-7.33 (m, 3H) 7.35-7.54 (m, 5H) 7.72 (m, d, J = 6.80 Hz, 2 H) 10.59 (s, 1 H)

Example AMD-6C2g;

(E) -2 ', 3', 4 ', 9' -tetrahydro-N, N-dimethyl-4- (3-fluorophenyl) -2 '- (2-phenylvinyl) carbonyl-spiro [ (1 '') - pyrido [3,4-b] indole] -4-amine (cis diastereomer)

To prepare the salt, the AMD-5c: amide amide (220 mg, 0.43 mmol) is dissolved in anhydrous aprotic solvent (1.5 mL) and citric acid (83 mg, 0.43 mmol), then treated with dissolution in the minimum amount of protic solvent possible. A non-polar solvent is then added dropwise to cause precipitation of the product. Subsequently, the solid is suction filtered, excluding air, and dried at 50 ° C in an oil vacuum pump. The product AMD-6C2S is obtained in a yield of 100 mg (33%).

Comparative Examples AMD-7C2S 2 ', 3', 4 ', 9' -tetrahydro-N, N-dimethyl-4- (3-fluoro-phenyl) -2 '- (3,4-dimethoxybenzyl) spiro [cyclohexane-1,1 '(1'H) -pyrido [3,4-b] indole] -4-amine (cis diastereomer)

The spiroamine AMN-2cis (200 mg, 0.54 mmol) is dissolved in a halogenated solvent (5 ml) in a suitable oven for 60 Ρ Ρ 2 598 503 / ΡΤ microns and treated with 2- (3,4-dimethoxyphenyl) (230 mg, 1.1 mmol) and diisopropylethylamine (138 mg, 1.1 mmol). The reaction mixture is maintained under microwave irradiation at 120 ° C for 10 min. (Initiator Eight, Signature Biotage). After completion of the reaction (monitored by TLC) the reaction mixture is first filtered, and then the mother liquor is treated with a solution of NaOH (5N, 10 ml). After separation of the phases the aqueous phase is extracted three times with a polar aprotic solvent (each time with 5 ml). The combined organic phases are dried over MgSO4 and concentrated. The crude product is purified by column chromatography. The AMD-7C2S product is obtained in 140 mg (47%) yield. 1 H NMR (600 MHz, DMSO-d 6) d ppm 1.54 (t, J = 12.46 Hz, 2 H) 1.79 (t, J = 13.22 Hz, 2 H) 1.85-1.96 ( (m, 6H) 2.52-2.60 (m, 2H) 2.62-2.72 (m, 2H) 2.73-2.89 (m, 2H) 3.74 (s, 3H) (S, 3H), 3.82 (br s, 2H) 3.90 (br s, 2H) 6.83-6.93 (m, 4H) 6.97 (t, J = 7.55 Hz 1H), 7.13 (t, J = 7.18 Hz, 1 H) 7.19 (d, J = 8.31 Hz, 1 H) 7.20-7.32 (m, 3H) 7.41-7 , 54 (m, 1 H) 10.53 (s, 1 H)

EXAMPLE 9 (E) -2 ', 3', 4 ', 9' -tetrahydro-N, N-dimethyl-6'-fluoro-4- (3-fluorophenyl) -2 '- (2- phenyl) carbonyl spiro [cyclohexane-1,1 '(1'H) -pyrido [3,4-b] indole] -4-amine (cis diastereomer)

In a microwave-safe vessel spiroamine AMN-3c: 1 (0.197 g, 0.5 mmol, 1 eq.) Is suspended in 15 ml of absolute DCM. To this suspension is added sequentially one after another ethyl diisopropylamine (0.129 g, 1 mmol, 2 eq.) And cinnamic acid chloride (0.166 g, 1 mmol, 61 ÅΡΡ 2 598 503 / æ 2 eq.). The vessel is then sealed and subjected to microwave radiation (Initiator Eight, Firm Biotage) for 10 min at 120 ° C. For further treatment the reaction mixture receives 4 ml of water and 4 ml of 1N sodium hydroxide solution. This mixture is stirred for 2 h at room temperature. The phases are then separated and the aqueous phase is extracted three times with DCM. The combined organic phases are then washed with water and dried over sodium sulfate. Then the solvent is removed under reduced pressure and the residue purified by column chromatography (silica gel, 1: 2 ethyl acetate / cyclohexane 1: 0). 0.0877 g of the AMD-8CiS product (33%) is thus obtained.

HPLC / MS analysis: Rt = 4.2 min; Purity (UV 200-400 nm) 97%; m / z = 526.1

Comparative examples AMD-9C2S 2 ', 3', 4 ', 9' -tetrahydro-N, N-dimethyl-6'-fluoro-4- (3-fluoro-phenyl) -2 '- (benzyl) -spiro [cyclohexane-1,1 '(1'H) -pyrido [3,4-b] indole] -4-amine (cis diastereomer)

In a suitable microwave vessel, a spiroamine AMN-3c: is (0.25 g, 0.63 mmol, 1 eq.) Suspended in 19 ml of abs. DCM. To this suspension are successively added ethyldiisopropylamine (0.163 g, 1.26 mmol, 2 eq) and 2-phenylacetyl chloride (0.195 g, 1.26 mmol, 2 eq) successively. The vessel is then sealed and radiated in the microwave (Initiator Eight, Firma Biotage) with heating for 10 min at 120 ° C. For further work up, the reaction mixture is mixed with 5 ml of water and 5 ml of 1N sodium hydroxide solution. This mixture is then stirred for 2 h at room temperature. 62 ΕΡ 2 598 503 / ΡΤ

The phases are then separated and the aqueous phase is extracted with DCM 3 times. The combined organic phases are washed with water and dried over sodium sulfate. After the solvent has been removed under reduced pressure, the residue is purified by column chromatography (silica gel: ethyl acetate / ethyl acetate / methanol 9: 1). 0.145 g of the product AMD-9C 2 S (45%) are thus obtained.

HPLC / MS analysis: Rt = 3.9 min; Purity (UV 200-400 nm) 98%; m / z = 514.1

EXAMPLE AMD-10CJS (E) -2 ', 3', 4 ', 9' -tetrahydro-N, N-dimethyl-6'-fluoro-4-phenyl-2 '- (2-phenylvinyl) carbonyl-spiro [ cyclohexane-1,1 '(1'H) -pyrido [3,4-b] indole] -4-amine (cis diastereomer)

To a solution of cinnamic acid chloride (0.198 g, 1.192 mmol, 3 eq) in 4.5 ml of absolute THF is added, under nitrogen atmosphere, a solution of spiroamine AMN-4c: , 15 g, 0.377 mmol, 1 eq.) In 9 mL of absolute THF. After stirring at room temperature for 1 h, the turbid reaction solution is then treated first with 3 ml of water and under ice-cooling with a further 3 ml of 1N sodium hydroxide solution. The mixture is then stirred for 1.5 h. Then the solvent is removed under reduced pressure and the precipitated solid is filtered and washed with water. The crude product is then purified by column chromatography (silica gel, ethyl acetate). 0.043 g of the product AMD-10C1S (21%) is thus obtained. 63 ΕΡ 2 598 503 / ΡΤ

HPLC / MS analysis: Rt = 4.2 min; Purity (UV 200-400 nm) 98%; m / z = 508.2

Comparative Example AMD-11c: is 2 ', 3', 4 ', 9' -tetrahydro-N, N-dimethyl-4- (3-fluorophenyl) -2'-benzylcarbonyl-spiro [cyclohexane- 1 '(1'H) -pyrido [3,4-b] indole] -4-amine (cis diastereomer)

The spiroamine cis AMN-2C 2 S (1.29 g, 3.4 mmol) is dissolved under oxygen-free conditions in absolute tetrahydrofuran (20 mL) and absolute dichloromethane (120 mL) treated with Hunig's base (1.167 mL, 6.8 mmol) and at room temperature was treated with 2-phenylacetyl chloride (900 μΐ, 6.8 mmol). After a reaction time of 30 min, the mixture is then treated with 5N sodium hydroxide solution (100 ml) and stirred for 2 h. The aqueous phase is then separated and extracted with dichloromethane (3x10 ml). The combined organic phases are then dried over Na2 SO4 &lt; 4 &gt; and then concentrated. There is thus isolated a crude product which is subjected and separated by chromatography [silica gel 60 (100 g); EtOAc (1000 mL)]. The AMD-11C1S cis amide is thus obtained in a yield of 82 mg (49%) with a melting point of 95-100 ° C as a colorless solid. 13 C-NMR (101 MHz, DMSO-D) ppm: 22.1, 29.1, 33.0, 38.0, 40.8, 43.1, 60.0, 60.3, 105.5, 111 , 1, 113.7, 113.2, 114.5, 114.7, 117.3, 118.4, 120.5, 123.8, 126.2, 126.5, 128.2, 129.0, 129 , 2, 129.3, 135.3, 136.5, 139.5, 140.6, 161.1, 163.5, 173.4 64 ΕΡ 2 598 503 / ΡΤ

Example AMD-12c: LS (E) -2 ', 3', 4 ', 9' -tetrahydro-N, N-dimethyl-4- (4-fluorophenyl) -2 '(2-phenylvinyl) carbonyl spiro [cyclohexane-1,1 '(1'H) -pyrido [3,4-b] indole] -4-amine (cis diastereomer)

To a suspension of spiroamine cis-AMN-5CiS (500 mg, 1.32 mmol) in absolute dichloromethane (40 ml) are added dropwise under an argon atmosphere at a time interval of 10 minutes successively one Hiinig (0.45 mL, 342 mg, 2.64 mmol) and cinnamic acid chloride (440 mg, 2.64 mmol) dissolved in absolute dichloromethane (12 mL). The reaction mixture is then stirred at room temperature for 1 h, then treated with water (30 ml) and 1N sodium hydroxide solution (5 ml) and stirred for 1.5 h. The dichloromethane is then removed under vacuum. In this way a light colored solid precipitate is obtained, which is separated by filtration and then washed with water (3x30 ml). This gives a crude product which is purified by chromatography (silica gel 60 (70 g), ethyl acetate / cyclohexane 1: 1 (500 ml), ethyl acetate (1000 ml), ethyl acetate / methanol 10: 1 (330 ml), 4: 1 ethyl acetate / methanol (800 ml), methanol (300 ml)]. To work up the crude product on the column it must be dissolved in 1: 1 ethyl acetate / cyclohexane with a little tetrahydrofuran. AMD-12CiS cis amide (m.p. 145-155 ° C) is then obtained as a colorless solid in 31% yield (204 mg, 0.40 mmol). 13C (ΤΗ) -NMR (101 MHz, DMSO-D 6) ppm: 22.5 (1 C), 29.3 (2 C), 32.6 (2 C), 37.8 (2 C) 3 (1 C), 59.5 (1 C), 60.3 (1 C, 65 ΕΡ 2 598 503 / ΡΤ br), 105.4 (1 C), 111.1 (1 C), 114.3 (1 C), 118.4 (1 C), 120.5 (1 C), 123.1 (1 C), 126.6 (1 C) (2C), 129.3 (2C), 129.8 (2C, d, J = 8Hz), 132.4 (1C, br) , 135.4 (1 C), 135.4 (1 C), 139.4 (1 C), 140.4 (1 C), 160.9 (1 C, d, J = 243 Hz) 3 (1 C) Synthesis of Comparative Examples of Trans Spiroamides (AMDtrans)

Comparative Examples AMD-3tra ss

2 ', 3', 4 ', 9' -tetrahydro-N, N-dimethyl-4- (3-fluoro-phenyl) -2 '- (benzothiophen-2-yl) carbonyl-spiro [ hexane-1,1 '(1'H) -pyrido [3,4-b] indole] -4-amine (1: 1) (trans diastereomer)

2 ', 3', 4 ', 9' -tetrahydro-N, N-dimethyl-4- (3-fluorophenyl) -2 '- (benzothiophen-2-yl) carbonyl spiro [cyclohexane- 1 (1H) -pyrido [3,4-b] indole] -4-amine (trans diastereoisomer) Benzo [b] thiophene-2-carboxylic acid chloride (728 mg, 3.96 mmol) under an atmosphere of argon is diluted in tetrahydrofuran abs. (30 mL) and treated at room temperature with the trans-AMN-2S-spiroamine (500 mg, 1.32 mmol) dissolved in absolute tetrahydrofuran. (60 ml) over 75 min. Here a slight precipitate is formed. After a reaction time of 2 h, the reaction mixture is diluted with water (15 ml) and ice-cooling is added 1N sodium hydroxide solution (15 ml) and stirred for 2.5 h. The tetrahydrofuran is then removed under vacuum. In this way a solid precipitates which is separated by filtration and is washed with water (3 x 20 ml). The crude product (587 mg) is 66 Å Ρ 2 598 503 / ΡΤ then separated by chromatography [silica gel 60 (80 g); ethyl acetate / cyclohexane 1: 1 (1L), 4: 1 ethyl acetate / methanol (500 ml)]. The trans amide is thus obtained as a colorless solid, in a yield of 12% (82 mg) having a melting point of 219-221 ° C. 13 C-NMR (101 MHz, CDCl 3) ppm: 22.4, 30.0, 30.9, 38.2, 46.4, 58.3, 59.5, 106.2, 111.0, 113.5 , 113.7, 114.4, 114.7, 118.0, 119.1, 121.4, 122.5, 123.1, 124.7, 125.5, 125.8, 126.4, 128 , 7, 136.0, 138.7, 140.1, 140.4, 141.1, 142.1, 161.2, 163.7, 167.1

2 ', 3', 4 ', 9' -tetrahydro-N, N-dimethyl-4- (3-fluoro-phenyl) -2 '- (benzothiophen-2-yl) carbonyl-spiro [ hexane-1,1 '(1'H) -pyrido [3,4-b] indole] -4-amine (1: 1) (trans diastereomer; AMD-3 trans) The trans amide produced so far (82 mg, mmol) is suspended in ethanol (8 mL) at 80 ° C and treated with a solution of ethanol (3 mL) and citric acid (32 mg, 0.167 mmol). From the clear solution a solid precipitate is obtained when subjected to cooling to room temperature. After 1.5 h the mixture is concentrated to 2 ml, then diethyl ether (20 ml) is added and the whole is stirred for 20 min. A colorless solid is separated and filtered off and washed with diethyl ether (2 x 3 ml) (64 mg). After 3 days at ambient temperature, further precipitated solid material is removed by filtration with suction and then washed with diethyl ether (2x2ml) (35mg). Both fractions are then combined. The trans-AMD-3rath citrate is thus obtained in 81% yield (89 mg) with a melting point of 175-185 ° C.

Comparative Examples AMD-6

(E) -2 ', 3', 4 ', 9' -tetrahydro-N, N-dimethyl-3-fluoro-phenyl) -2 '- (2-phenylvinyl) carbonyl-spiro [cyclohexan-1 , 1 '(1'H) -pyrido [3,4-b] indole] -4-amine (1: 1) (trans diastereomer): Î »P 2 598 503 / ΡΤ

2 ', 3', 4 ', 9' -tetrahydro-N, N-dimethyl-4- (3-fluorophenyl) -2 '- (2-phenylvinyl) carbonyl-spiro [cyclohexane-1,1' 1 H) -pyrido [3,4-b] indole] -4-amine hydrochloride (trans diastereomer) The cinnamic acid chloride (1.32 g, 7.92 mmol) is diluted in absolute tetrahydrofuran. (30 ml) under argon atmosphere and at room temperature added with contaminated AMN-2 C2 S spiroamine (1.0 g, 2.64 mmol, containing about 10% trans AMN-2 diastereoisomer) dissolved in abs. Tetrahydrofuran. (60 ml) over 40 min. After a reaction time of 1 h, water (20 ml) is added to the turbid reaction solution and under ice-cooling, 1N sodium hydroxide solution (20 ml), all stirred for 1.5 h. The tetrahydrofuran is then removed under vacuum. Under these conditions a solid is precipitated which is filtered off and washed with water (3 x 25 ml). The crude product (1.16 g) is separated by chromatography [silica gel 60 (200 g); ethyl acetate / cyclohexane 1: 1 (1.3 L), ethyl acetate (1.6 L)]. The cis amide is obtained as a colorless solid in 40% yield (540 mg) having a melting point of 155-158 ° C. The trans amide is obtained and isolated in 7% yield (93 mg) with a melting point of 151-155 ° C.

2 ', 3', 4 ', 9' -tetrahydro-N, N-dimethyl-4- (3-fluoro-phenyl) -2 '- (2-phenylvinyl) carbonyl-spiro [cyclohexane-1 The trans amide barely obtained (188 mg, 0.37 mmol) was obtained as a white solid (1: 1) (1 H) is then dissolved at 80 ° C in ethanol (35 ml) and an ethanolic solution (2 ml) of citric acid (77 mg, 0.4 mmol) is added. 68 ΕΡ 2 598 503 / ΡΤ

All is stirred at room temperature for 2 h, which begins gradually after crystallization. The mixture is then held at 5 ° C for 1.5 h, the resulting colorless solid collected and separated by filtration and washed with diethyl ether (3 x 3 mL) (146 mg). The filtrate is then concentrated, taken up in ethanol (1 ml) and treated with diethyl ether (20 ml). After 16 h further colorless salt is then separated and washed with diethyl ether (2 x 2 ml) (36 mg). Both fractions are combined and trans-AMD-6tracyl citrate is obtained in 71% yield (182 mg) having a melting point of 161-164 ° C. 13 C-NMR (101 MHz, DMSO-D 6) ppm: (trans diastereomer) 22.4,

Comparative Examples 2 ', 3', 4 ', 9' -tetrahydro-N, N-dimethyl-4- (3-fluorophenyl) -2 '- (3,4-dimethoxybenzyl) carbonyl spiro [ cyclohexane-1,1 '(1'H) -pyrido [3,4-b] indole] -4-amine (trans diastereomer)

RAC

3,4-Dimethoxyphenylacetic acid (1 g, 5.1 mmol, 2.2 eq.) Is suspended in 25 ml of abs. Toluene. and thionyl chloride (0.84 mL, 11.6 mmol, 5.0 eq.) is added. All is heated for 2 hours under reflux, and then the solvent is removed. The residue is co-distilled along with abs. Toluene. (3 x 50 ml) and the crude product dissolved in dichloromethane (37 ml) and transferred to a microwave-suitable vessel. Then, spiroamine AMN-2β 69 690 503 / ΡΤ (0.875 mg, 2.32 mmol) and Hiinig base (0.78 ml, 580 mmol, 250 eq.) Is introduced, the vessel is then sealed and subjected to microwave radiation (Initiator Eight, Firma Biotage) with heating for 20 min at 120 ° C. To work up to the reaction mixture is added 17 ml of water and 17 ml of 1N sodium hydroxide solution. This mixture is stirred for 2 h at room temperature. Then the phases are separated and the aqueous phase is extracted with 3x dichloromethane. The combined organic phases are then washed with water and dried over sodium sulfate. The solvent is then removed under reduced pressure and the residue is purified by column chromatography (silica gel, ethyl acetate / n-hexane 2: 1). There is thus obtained 0.236 g of the product is AMD-7α-5S (18%).

HPLC / MS analysis: Rt = 5.45 min; Purity (UV 200-400nm) &gt;99%; m / z = 555.8 Synthesis of Comparative Examples of cis Spiroethers (ETERcis)

Comparative Example ETER-1C2S

6 '-fluoro-4', 9'-dihydro-N, N-dimethyl-4- (3-thienyl) -spiro [cyclohexane-1,1 '(3'H) -pyrano [3 , 4-amino] -4-amine, (2: 5) (cis diastereomer)

Ketone E-5 (446.6 mg, 2 mmol) is combined with 5-Fluor-tryptophol (2.394.4 mg, 2 mmol) all dissolved in absolute 1,2-dichloroethane (30 mL). The mixture is then treated with methane sulfonic acid (0.13 mL, 2 mmol) whereupon the color of the reaction solution changes from red-brown to dark gray. After 5 minutes we have the formation of a light gray solid that begins to precipitate. The mixture is then stirred at room temperature for 20 h. Then, the cis spiroether methanesulfonate is suction filtered and washed with 1,2-dichloroethane (2 x 10 ml). The gray solid is obtained in 76% yield (733 mg) and a melting point of 143-145 ° C (ETER-1: 1). The filtrate is then treated with 1N NaOH solution (30 ml) and stirred at room temperature for 2h. In this way the trans spiroheter precipitates as a colorless solid and is obtained after filtration in 8% yield (58.5 mg). NMR (600 MHz, DMSO-d6): 1.67 (m, 2H) 1.94 (m, 2H) 2.24 (m, 2H) 2.44 (s, 8H) 2.53 (s, 3H) 2.54 (s, 3H), 2.66 (t, J = 5.27

J = 5.28 Hz, 2 H) 6.84 (m, 1 H) 7.14 (m, 1 H) 7.19 (dd, J = = 4.50 / 8.70 Hz, 1 H) 7.47 (d, J = 5.10

1H), 8.07 (m, 1H), 9.67 (m, 1H), 10.80 (s, 1H)

Comparative Example ETER-2C2S

4 ', 9' -dihydro-N, N-dimethyl-4- (2-thienyl) -spiro [cyclohexane-1,1 '(3'H) -pyrano [3,4- b] indole] -4-amine, (1: 2) (cis diastereomer)

Ketone E-4 (223 mg, 1 mmol) is placed together with tryptofol (2.161 mg, 1 mmol) in absolute dichloromethane (40 mL). Then methanesulfonic acid (0.071 ml, 1.1 mmol) is added. The mixture is then stirred at room temperature for 16 h, thereby precipitating the spiroether methanesulfonate. The light gray solid (ETER-2c: is) is thus collected by filtration, washed with dichloromethane (2x10ml) and recovered in 25% yield (117mg) having a melting point of 132øC. The filtrate is then treated with 1N NaOH solution (20 mL) and stirred at room temperature for 16 h. The organic phase is separated and the aqueous phase is extracted with dichloromethane (2 x 20 ml). The organic phases are combined, dried and concentrated. In this case a mixture of substances (284 mg) is obtained, which is subjected to chromatographic separation (silica gel G (20 g); ethyl acetate / methanol 8: 1]. The trans spiroheter is thus obtained in 54% yield (196 mg, m.p. 235-238 ° C) and cis spiro ether in 10% yield (38 mg). NMR (600 ΜΗζ, DMSO-d 6) 1.82 (m, 2 1,) 1.98 (m, 2 2,3) 2.33 (m, 2H) 2.36 (s, 6H) (T, J = 5.23 Hz, 2 H), 2.60 (s, 3H), 2.61 (s, 2H) 6.94 (m, 1H) 7.00 (m, 1H) 7.21 (d, J = 8.29 Hz, 1 H) 7.34 (dd, J = 3.14 / 5.28 Hz, 1H) 7.37 (d, J = 7.37 Hz, 1 H) 7.59 (d, J = 2.76

(D, J = 5.32 Hz, 1 H) 9.78 (m, 1 H) 10.74 (s, 1 H)

Devices and methods for HPLC-MS analysis: HPLC: Waters Alliance 2795 with Waters 996 PDA; MS: ZQ 2000 MassLynx Single Quadruple MS Detector; Column: Waters Atlantis ™ dC18, 3 pm, 2.1 x 30 mm; Column temperature: 40 ° C, Eluent A: purified water + 0.1% formic acid; Eluent B: acetonitrile (gradient grade) + 0.1% formic acid; 0% gradient from B to 100% B in 8.8 min, 100% B for 0.4 min, 100% B at 0% B in 0.01 min, 0% B for 0.8 min; Flow: 1.0 mL / min; Ionization: ES +, 25 V; Make up: 100 μΐ / min 70% methanol + 0.2% formic acid; UV: 200-400 nm

Investigation of the Pharmacological Properties of the Compounds of Examples A) Comparison of analgesic efficacy (as ED50 or% MPE for a given test dosage) in acute pain models (tail-withdrawal test, mice / mice) and mono- neuropathic (Chung, rats; Bennett, rats) or poly neuropathic pain model (STZ polyneuropathy, rats).

In order to describe the surprising pharmacological properties of the compounds within the scope of the present invention, the results of the Chung monkey neuropathic pain model in rats should be compared first and foremost with the acute pain model with withdrawal from tip of the tail in rat. Here it can be demonstrated that the compounds within the scope of the present invention in a multiple dosage of the effective effective analgesic dosage according to the Chung model (for example ED50n), do not have any significant anti-nociceptive effect on the tail withdrawal model of the mouse. The results of other models of neuropathic pain, such as the Bennett model in rats or STZ polyneuropathy in the rat, generally underline very good efficacy of the compounds in various forms of neuropathic pain. 72 ΕΡ 2 598 503 / ΡΤ

Analgesic test using the tail withdrawal test in rats

Animals in test: Female rats according to Sprague Dawley (cre: CD (SD) non-breeding; breeder: Charles River, Sulzfeld, Germany); Body weight: 130-190 g; the animals are kept in standard cages (Makrolon type IV cages, Ebeco F, Castrop-Rauxel, Germany) containing a maximum of 8 animals in each, under a rate of light incidence periods: absence of light from 12: 12h with food and running tap water ad libitum (at will).

Description of the method: The analgesic activity of the test compounds is investigated using the thermal focus method (in the tail withdrawal test) in rats according to the method of D 'Amour and Smith (J. Pharm. Exp. Ther. 72 , 74, 79 (1941)). The animals are individually placed in special test cages and exposed at the base of the tail to a focused beam of radiation from a lamp (withdrawal of tail type 50/08 / 1.bc, Labtec, Dr. Hess). The lamp intensity is adjusted so that the time from when the lamp is switched on until the tail is withdrawn (withdrawal latency) in untreated animals is 2.5 to 5 seconds. Before administration of a test compound, the animals are pretested twice within a time interval of 30 minutes and the mean value of these measurements is taken as the mean of the pre-test. Pain measurement is usually done after 5, 20, 40, 60, 90, 120, 180 and 240 minutes following intravenous administration of the test compound or vehicle. The antinociceptive effect is determined as the increase in withdrawal latency time according to the following formula: (% MPE) = [(Ti-To) / (T2-T0)] 100. Where: T0: latency time control before substance administration, Ti: latency time after substance administration, T2: maximum exposure time of thermal focus (12 seconds), MPE (maximum possible effect): maximum possible effect .

In test compounds effective for anti-nociceptive cases are used to determine dose dependence, 3 to 5 logarithmically increasing dosage doses, which included threshold dose and maximum effective dose values. 73 ΕΡ 2 598 503 / ΡΤ The effective dose corresponding to half the maximum (ED50) with the corresponding 95% confidence intervals is determined by semi-logarithmic regression analysis, at the time of maximum effect.

Statistical analysis: The dimensions of the groups are typically n = 10. Through repeated measures analysis (repeated measures: ANOVA) as well as post hoc analysis according to Bonferroni, the statistically significant differences in the% MPE values between the respective dosage groups and the groups were tested control system. The significance level set is &lt; 0.05.

Tail removal test with reduced intensity of the thermal radiation in the rat

Animals under test: rats according to Sprague-Dawley (breeder: Janvier, Le Genest St Isle, France); Body weight: 200-250 g; the animals are kept in standard cages (Makrolon type IV cages, Ebeco F, Castrop-Rauxel, Germany) with a maximum of 5 animals per cage, with a rate of light incidence periods: no light of 12: 12h with food and running water ad libitum.

Description of the method: Modulating activity of test substances for acute noxious thermal stimuli is investigated in the thermal focus test (tail withdrawal test) in test mice according to the method of D 'Amour and Smith (J. Pharm. Exp. Ther., 72, 74-79 (1941)). These are thus used. The animals are individually placed in special test compartments and the base of the tail is exposed to a beam of thermal radiation centered by a focal analgesimeter (model 2011, Rhema Labortechnik, Hofheim, Germany). The intensity of the focal heat beam is adjusted so that the time elapsing between the beginning of the thermal beam action and the sudden tail withdrawal (withdrawal latency) in untreated animals is about 12-13 seconds. Prior to the administration of a substance within the scope of the present invention, withdrawal latency is determined twice at five minute intervals and the mean latency withdrawal value is defined as the mean value of 74 ΕΡ 2 598 503 / ΡΤ control. Measurement of tail withdrawal latency is performed for the first time 10 minutes after intravenous administration of the test compound or vehicle. After the antinociceptive effect has subsided (after 2-4 hours) the studies and measurements are then performed at intervals of 30 minutes to a maximum of 6.5 hours after administration of the test substance. The anti-or pro-nociceptive effect is determined as the increase or decrease in withdrawal latency time according to the following formula: (% MPE) = ((1 ^ -To) / (T2-T0)] x100. we have T0: control latency time, before substance administration, Ti: latency time after substance administration, T2: maximum exposure time to thermal focus (30 seconds), MPE: maximum possible effect. of antinociceptive efficiency is applied to determine dose dependence, 3 to 5 logarithmically increasing dosage doses, which include the threshold dose and the maximum effective dose. The effective dose corresponding to half the maximum (ED50) with the corresponding confidence intervals of 95% is then determined by semi-logarithmic regression analysis, at the time of maximum effect.

Statistical analysis: The dimensions of the groups are typically n = 10 Through analysis of variance with repeated measurements (repeated measures ANOVA) as well as post hoc analysis according to Bonferroni, for statistically significant differences, the data of% MPE between the dosage groups and vehicle control groups. The established level of significance is p &lt; 0.05.

Proof of analgesics in the tail withdrawal test in mice

Animals under test: male RMNI mice (breeder: Charles River, Sulzfeld, Germany); Body weight: 20-25 g; the animals are kept in standard cages (Makrolon type III cages, Ebeco, Castrop-Rauxel, Germany) with a maximum of 6 animals per cage, with a rate of light incidence periods: absence of light from 12: 12h with food and tap water ad libitum. 75 ΕΡ 2 598 503 / ΡΤ

Description of the method: The analgesic efficiency of the test compound is examined with the thermal focus test (tail removal) in mice according to the method of D 'Amour and Smith (J. Pharm. Exp. Ther. (1941) The animals are individually placed in special test cages and the base of the tail focused with thermal radiation from an electric lamp (tail-type test 55/12 / 10fl, Labtec, Dr. Hess) The intensity of the lamp is adjusted so that the time from light of the lamp to the sudden withdrawal of the tail (withdrawal latency) in untreated animals is 2.5-5 seconds. , animals are pre-tested at the time interval of 30 minutes twice and the mean of these measurements is taken as the mean of the pre-test. Pain measurement is typically performed at 20, 40 and 60 min following intravenous administration of the test compound or of its vehicle. ciceptivo is determined as the increase in withdrawal latency time according to the following formula: (% MPE) = [(Ti-T0) / (T2-T0)] 100. Where T0: latency time control before substance administration, Ti: latency after substance administration, T2: maximum exposure time to thermal focus (12 seconds), MPE: maximum possible effect. In antinociceptive efficiency test compounds, 3 to 5 logarithmically increasing dosage doses, which include the threshold dose and the maximum effective dose, are applied to determine dose dependence. The efficient dose corresponding to half the maximum (ED 50) with the corresponding 95% confidence intervals is then determined by semi-logarithmic regression analysis, at the time of maximum effect.

Statistical analysis: The dimensions of the groups are typically n = 10 Through analysis of variance with repeated measurements (repeated measures ANOVA) as well as post hoc analysis according to Bonferroni, for statistically significant differences, the data of% MPE between the dosage groups and vehicle control groups. The established level of significance is p &lt; 0.05. 76 ΕΡ 2 598 503 / ΡΤ

Chung model: Mononeuropathic pain after spinal nerve attachment

Animals in the test: male Sprague Dawley rats (RjHan: non-conspecific SD, breeder: Janvier, Genest St Isle, France); with a body weight: 140-160 g are kept in standard cages (Makrolon Type IV cages, Ebeco F, Castrop-Rauxel, Germany) with a maximum of 8 animals per cage, with a rate of light incidence periods: absence of 12: 12h light with food and tap water ad libitum. Between the delivery of the animals and the operation, a pause of one week is observed. The animals are tested several times after surgery over a period of 4-5 weeks, where a cleaning period of at least one week is observed.

Description of the model: Under anesthesia with pentobarbital (Narcoren®, 60 mg / kg ip, Merial GmbH, Hallbergmoos, Germany) the spinal nerves L5, L6 are exposed in which a piece of the para-vertebral musculature is removed and a part of the process of the L5 spinal vertebral body. The spinal nerves L5 and L6 are carefully isolated and attached with a fixed ligature (black NC silk, USP 5/0, metric 1, Braun, Melsungen, Germany) (Kim and Chung, 1992). After ligation, the muscle and adjacent tissues were sutured and the wound closed with metal clips. After the recovery period of one week, the animals were placed for the measurement of mechanical allodynia in cages with a wire floor. The withdrawal time thresholds are then determined on the ipsilateral and / or contralateral hind legs with the use of an electronic von Frey filament (Somedic AB, Malmö, Sweden). The average of five stimulation according to this process gives us a certain point. The animals are then tested 30 min before and at various times after administration of test substance or carrier solution. The data are determined as% maximal effect MPE of pre-test with individual animals (= 0% MPE) and test values of an independent simulated control group (= 100% MPE). Alternatively, withdrawal thresholds are plotted in grams. In analgesic effect test compounds 3 to 5 logarithmically increasing dosage doses are used to determine the dose dependence to be administered, which includes the threshold and the maximum effective dose, to determine 77 ± 5 598 503 / depend. The effective dose corresponding to half the maximum (ED50) with the corresponding 95% confidence intervals is determined by semi-logarithmic regression analysis at the time of maximum effect.

Statistical analysis: The dimensions of the groups are typically n = 10 Through analysis of variance with repeated measurements (repeated measures ANOVA) as well as post hoc analysis according to Bonferroni, for statistically significant differences, the data of% MPE between the dosage groups and vehicle control groups. The established significance level is p &lt; 0.05.

Reference: Kim, S.H. and Chung, J.M., An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat, Pain, 50 (1992) 355-363.

Bennett Model: Mononeuropathic pain in the rat

Animals in the test: male Sprague Dawley rats (RjHan: non-conspecific SD, breeder: Janvier, Genest St Isle, France); with a body weight: 140-160 g are kept in standard cages (Makrolon Type IV cages, Ebeco F, Castrop-Rauxel, Germany) with a maximum of 8 animals per cage, with a rate of light incidence periods: absence of 12: 12h light with food and tap water ad libitum. Between the delivery of the animals and the operation, a pause of one week is observed. The animals are tested several times after surgery over a period of 4-5 weeks, where a cleaning period of at least one week is observed.

Description of the method: Investigation of efficacy in neuropathic pain was performed according to the Bennett model (chronic constriction injury; Bennett and Xie, 1988, Pain 33: 87-107). Rats are supplied under Narcoren anesthesia with four loose ligaments of the right sciatic nerve. The animals develop a hypersensitivity which, after a recovery period, is determined from one to about four weeks, by means of a cold metal plate at 4øC (78 ÅΡ 59 598 503 / al cold allodynia) in the paw innervated by damaged nerve. The animals are observed for a period of 2 min. on this plate and the number of withdrawal reactions of the injured paw is measured.

Assessment and statistics: For the preliminary value before application of the substance, the effect of the test substance is determined over a period of one hour at four time points (eg 15, 30, 45, 60 minutes after application ) and the resulting area under the curve (AUC) as well as the inhibition of cold allodynia at the individual measurement points is expressed as a percentage of effect on the control vehicle (AUC) or the (individual) starting or starting value. A The size of the group is n = 10, the significance of an anti-allodynic effect (p &lt; 0.05) is determined using a repeated measures variance analysis and Bonferroni post hoc analysis.

STZ model: Polyneuropathic pain in the rat

Animals under test: Male Sprague Dawley rats (breeder: Janvier, Le Genest St. Isle, France); with a body weight: 140-160 g are kept in standard cages (Makrolon Type IV cages, Ebeco F, Castrop-Rauxel, Germany) with a maximum of 8 animals per cage, with a rate of light incidence periods: absence of 12: 12h light with food and tap water ad libitum.

Method Description: For the induction of diabetes, streptozotocin (STZ, 75 mg / kg) was injected intraperitoneally into male Sprague-Dawley rats. Diabetic rats then have a blood glucose level of at least 17 mM per week after STZ injection. Control animals are injected with vehicle solution. The determination of nociceptive mechanical stimulus threshold (in grams) is performed with an algesiometer (instrument to determine the sensitivity of the skin to painful stimuli) in paw pressure test according to Randall and Selitto (1957). In this case, an increasing pressure stimulus is applied to the dorsal surface of the hind paw and the pressure exerted leading finally to the withdrawal reflex or a vocalization is recorded. The tests are performed three weeks after the 79 ΕΡ 2 598 503 / ΡΤ induction of diabetes. The mechanical nociceptive threshold is measured before, as well as 15, 30, 45 and 60 minutes after the test substance is administered to diabetic animals and control animals.

References: Randall LO, Selitto JJ. A method for measurement of analgesic activity on inflamed tissue. Arch. Int. Pharamcodyn. 1957; 111: 409-19. B) Comparison of the effective analgesic dose range in mono-neuropathic pain models (Chung, rats) with observation of the typical side effects of opioids in this range of dosages.

In order to describe the surprising pharmacological properties of the compounds within the present invention, they are first compared with each other, the results of the Chung model in rats (as an example for analgesic efficacy against neuropathic pain) and analysis model of (such as respiratory depression, as a very serious, yet well-concealed, typical side effect of opioids). In these cases it can be shown that compounds within the scope of the present invention, even at multiple dosages of the significantly efficient analgesic effect of the Chung model (for example ED50n), do not cause any significant respiratory depression in rats. The results of other models of typical opioid side effects, such as circulatory parameters in rabbits, gastrointestinal carbon passage in rats, RotaRod test in rats, jumping test in rats, as well as conditioned preferential location in rats, emphasize general or very poor reduced typical opioid side effects of the compounds within the scope of the present invention.

Arterial gasometry: Method for measuring pC02- arterial and p02- in rats The effect of respiratory depression on test substances is examined after i.v. administration in instrumented conscious rats. Test parameter is the change in the partial pressure of carbon dioxide (pCC &gt; 2) and the partial pressure of oxygen (p02) in arterial blood after the administration of the substance.

Animals under test: Male Sprague Dawley rats (cri: non-blooded CD (creator: Charles River, Sulzfeld, Germany); with a body weight: 250-275g are kept in standard cages (Makrolon type II cages, Ebeco, Castrop-Rauxel, Germany) with a rate of light incidence periods: absence of 12: 12h light with food and tap water ad libitum.

Description of the method: At least 6 days before the test substance is applied, the mice are implanted under pentobarbital anesthesia with a PP catheter within the femoral artery and jugular vein. The catheters are filled with heparin solution (4000 IU) and sealed with a metal rod. Application of the test substance or vehicle is performed through the venous catheter. Prior to the application of the substance or vehicle and at defined time points after application of the substance or vehicle, the arterial catheter is in each case opened and washed with 500 μΐ of a heparin solution. They are then removed and recorded ca. 100 μl of blood from the catheter using a heparinized glass capillary. The catheter is then again washed with the heparin solution and again closed. Arterial blood is immediately measured using a blood gas analyzer (ABL 5, Radiometer GmbH, Willich, Germany). After a minimum recovery time of one week, the animals can be retested.

Analysis of test data and statistics: The blood gas analyzer automatically provides the values for pC02 and p02 of blood in mmHg. The effects of the substance on partial pressure in the blood are calculated as the percentage changes from previous values without substance or vehicle use. For statistical analysis, the values measured after the administration of the substance and the values of the simultaneous measurements after vehicle administration are compared by means of one-way ANOVA analysis, as well as a post hoc analysis according to Dunnett. The level of significance is set at p <0.05. The dimensions of the groups are generally n = 6. 81 ΕΡ 2 598 503 / ΡΤ

Cardiovascular parameters: Method for the measurement of blood pressure and heart rate in conscious rabbits. The effect of test substances on the cardiovascular system is investigated following i.v. administration in conscious rabbits, monitored by remote transmission or telemetry. Test parameters are changes in heart rate and blood pressure following administration of the substance.

Animals in test: female rabbits (New Zealand whites; breeder: Charles River, Kisslegg, Germany); with a body weight: about 3-5.5 kg; the animals are kept in individual special rabbit cages (Width (W) x (depth (D) x (height (H) = 885x775x600 mm; Ebeco, Castrop-Rauxel, Germany) with a rate of light incidence periods : no light from 12: 12h with food and tap water ad libitum.

Assay preparation: At least 21 days before the start of the tests, a telemetry unit (TL11M2-D70-PCT manufactured by DSI, St. Paul, Minnesota, is implanted to each animal under general anesthesia (isoflurane 2-3%). , USA) for the measurement of blood pressure and electrocardiogram (ECG). In this case the telemetry unit pressure catheter is inserted into the femoral artery and both biopotential electrodes are fixed subcutaneously in the region of the external or the left upper thoracic wall region. The transmission unit is sutured into a subcutaneous pocket in the left flank region of the animals. Reception and recording of the telemetric signals are done via the receiver type RMC-1 (Signature DSI). For the reception of data, its storage and processing is used the software package Po-Ne-Mah (Signature DSI).

Experimental procedure: The application of the substance or the vehicle is performed through a venous catheter (atrial V.). Prior to the application of the test substance or vehicle and at defined time points after application of the substance or the vehicle, the values of the heart rate and arterial pressure (systolic, diastolic and mean) are measured and electronically stored directly transmitted through the calibrated telemetry system. After a minimum recovery time of one week, the animals can be put back into tests.

Analysis of test data and statistics: From the measured values for blood pressure (in mmHg) and heart rate (in beats per minute), in the defined time points, the mean value of 10 is transmitted in each case, beats. The effects of the test substance on the test parameters are calculated as the percentage variations from the previous values without use of the substance or vehicle. For statistical analysis, values measured after substance administration and simultaneous measurement values after vehicle administration are compared by one-way ANOVA. As well as post hoc analysis according to Dunnett. The level of significance is set at p <0.05. The dimensions of the groups are generally n = 6

Coal passage test: Method for measuring the gastrointestinal transit rate in rats

Animals under test: male RMNI mice (breeder: Charles River, Sulzfeld, Germany); Body weight: 30-35 g; the animals are kept in standard cages (Makrolon Type IV cages, Ebeco F, Castrop-Rauxel, Germany) with a maximum of 18 animals per cage, with a rate of light incidence periods: absence of light from 12: 12h with food and tap water ad libitum.

Test Description: Prior to the test, animals are fasted for 20 to 24 hours within the grid cages. A suspension of activated carbon (10% activated charcoal in 0.5% CMC solution, application volume: 0.1 ml / 10 g body weight) is administered orally to the animals as an intestinal transit marker. After this process the respective solution of test substance or vehicle is administered intravenously in each case. Two hours after the administration of activated charcoal suspension, the animals are sacrificed by CO2 fumigation. 83 ΕΡ 2 598 503 / ΡΤ

Subsequently, the intestinal tract from the stomach to the onset of the large intestine or cecum is withdrawn and spread on a glass plate moistened with a 0.9% NaCl solution. Immediately afterwards, the pylorus distance (outlet channel of the stomach) is measured to the cecum, as well as the route of passage of the coal suspension (its farthest point).

Test data analysis: To determine the relative inhibition of gastrointestinal transit, the quotient of the charcoal suspension pathway (in cm) / pinhole-cecum distance (in cm) is calculated. The result should be expressed as% inhibition. For statistical analysis, the values measured after the administration of the substance should be compared with the values of the simultaneous measurements after vehicle administration by means of one-way ANOVA analysis as well as a post hoc analysis of according to Dunnett. The level of significance is set at p <0.05. The dimensions of the groups are generally n = 10.

Rota-Rod test: method for the study of motor coordination in rats

Animals in test: Male rats CD-I (breeder: Charles River, Sulzfeld, Germany); Body weight: 18-25 g; the animals are housed in standard cages (Makrolon type IV cages, Ebeco F, Castrop-Rauxel, Germany) containing a maximum of 18 animals in each, under a rate of light incidence periods: absence of light from 12: 12h with food and running tap water ad libitum.

Description of the method: To describe the method, see: Kuribara H., Higuchi Y., Tadokoro S. (1977), Effects of central depressants on Rota-Rod and traction performance in mice. Japan. J. Pharmacol. 27, 117-126.

Statistical analysis: For the statistical analysis, the values measured after the administration of the substance and the values of the simultaneous measurements after vehicle administration are compared by means of one-way ANOVA analysis, as well as one-way post analysis 84 ΕΡ 2 598 503 / ΡΤ hoc according to Dunnett. The level of significance is set at p <0.05. The dimensions of the groups are generally n = 10.

Jumping test: method for the study of the potential of physical dependence in the mouse

Animals under test: Male RMNI rats (breeder: Charles River, Sulzfeld, Germany); Body weight: 20-24 g; the animals are kept in standard cages (Makrolon type III cages, Ebeco, Castrop-Rauxel, Germany) with a maximum of 6 animals per cage, with a rate of light incidence periods: absence of light from 12: 12h with food and tap water ad libitum.

Description of the method: The test substances are administered a total of seven times within two days by intraperitoneal application. On the first day, there are 5 applications: 9:00 a.m., 10:00 a.m., 1:00 p.m., 1:00 p.m. and 3:00 p.m., and on the second day at 9:00 a.m. and 11:00 p.m. The first three applications are given in dosages with increasing dosages (dosing scheme) and then in the other dosages equal to that of the third application. The withdrawal is performed immediately 2 hours after the last application of the substance with naloxone 30 mg / kg (i.p.). Continuous, the animals are observed individually in transparent observation boxes (height 40 cm, diameter 15 cm) and the jumping reactions are counted for 15 minutes in each 5 minute period. Morphine is applied in a dosage as a comparison / standard. The withdrawal quantification is performed on the number of jumps between 0 and 10 min. after the application of Naloxon. The number of animals per group with more than 10 jumps / 10 min is determined and is recorded as &quot;% positive animals &quot;. In addition, the average jump frequency is calculated in the group.

Statistical analysis: Analysis of the experimental results with respect to the statistically significant differences between each dosage group and the vehicle control group is preferably performed by Fisher's exact test &quot;% positive animals &quot; as well as by means of the Kruskal-Wallis test for the &quot; hop frequency &quot; parameter, preferably as described in the experimental part 85 ΕΡ 2 598 503 /.. In this case, the level of significance is set at p <0.05. The group dimensions are generally n = 12.

Reference: Saelens JK, Arch Int Pharmacodyn 190: 213-218, 1971

Conditioned positioning preference: a method to study the possible induction of psychological dependence / addiction or withdrawal in the rat

Description of the method: Investigation of the preferred site see: Tzschentke, T.M., Bruckmann, W. and Friedrichs, F. (2002) Lack of sensitization during place conditioning in rats is consistent with the low abuse potential of tramadol. Neuroscience Letters 329, 25-28.

Statistical analysis: Analysis of the experimental results in terms of statistically significant differences in the preference of the animals for an active substance or per vehicle is preferably performed by means of paired t-test, where the significance level is set at p <0 , 05. The dimensions of the groups are generally n = 8.

Table 1: Summary of pharmacological data for example AMD-6C2S

System under test Parameter measured Result 1 Distortion factor 2 Receptor binding ORL-1 Linking affinity Ki = 0.030 μΜ - P-Opioid receptor binding Ki affinity = 0.138 μm - Rats according to Chung The inhibition of neuropathic pain in mono-neuropathy (separation of anti-allodynic and anti-nociceptive effect) ED50 = 9 μg / kg iv; up to the highest dose tested (21.5 μg / kg i.v.): No anti-nociceptive effect on healthy tissues. - Rats according to Bennett Inhibition of neuropathic pain in mononeuropathy situations ED50 = 7 pg / kg i.v. - Rats in STZ Inhibition of neuropathic pain in diabetic polyneuropathy ED50 ca. 1 pg / kg i.v .; up to the highest dose tested (10 pg / kg i.v.): No anti-nociceptive effect in neuropathically uncontrolled situations. - 86 ΕΡ 2 598 503 / ΡΤ

System under test Measured parameter Result 1 Away factor 2 Tail withdrawal test Inhibition of acute pain (nociceptive pain) NOEL: 1 mg / kg iv or 4.64 mg / kg iv in situations of reduced thermal focus intensity 220-lOOOx Analysis of arterial gas in rats Respiratory depression as measured by increased arterial pC02 and decreased arterial p02 NOEL: 1 mg / kg iv 220x Cardiovascular analysis in rabbits Arterial blood pressure and heart rate NOEL: 1 mg / kg iv 220x Coal passage in rats Gastrointestinal tract NOEL: 3 mg / kg iv 660x RotaRod test in rats NOEL motor coordination:> 10 mg / kg iv> 2200x Jumping test in rats Symptoms of physical dependence / abstinence NOEL: 10 mg / kg ip 2200x Preferred Positioning in rats Physical dependence NOEL:> 13.8 mg / kg i.p. > 3000x NOEL (&quot; = No Observed Effect Mild) indicates the highest dose-free test results (i.e., the dose without significant effect) 2) The clearance factors are calculated as the NOEL ratio and ED5011 value of the neuropathy models (in this case: 4.5 pg / kg) mean at 87 ΕΡ 2 598 503 / ΡΤ

Table 1b: Summary of pharmacological data for example AMD-7CiS (Comparative Example)

System under test Measured parameter Result 1 Distal factor 2 Receptor binding ORL-1 Linking affinity Ki = 0.070 μΜ - P-Opioid receptor binding Ki affinity = 0.450 μΜ - Rats according to Chung Inhibition of neuropathic pain in mononeuropathy (separation of anti-allodynic and anti-nociceptive effect) ED 50 = 88 μg / kg iv; No anti-nociceptive effect in healthy tissues (test dosage: 100 pg / kg i.v.) - Rats in STZ Inhibition of neuropathic pain in diabetic polyneuropathy 68% MPE at 100 pg / kg i.p .; No anti-nociceptive effect in neuropathically uncontrolled situations - Tail withdrawal test Acute pain inhibition (nociceptive pain) NOEL: &gt; 10 mg / kg iv &gt; 11 Ox Arterial gas analysis in rats Respiratory depression measured by increase in arterial pC02 and decrease in arterial p02 NOEL: 1 mg / kg iv llx Cardiovascular analysis in rabbits Blood pressure and heart rate NOEL:> 3 mg / kg iv> 34x Coal passage in rats NOEL gastrointestinal tract: 1 mg / kg iv llx RotaRod test in rats NOEL motor coordination: 10 mg / kg iv HOx Jumping test in rats Symptoms of physical dependence / abstinence NOEL:> 10 mg / kg ip &gt; 11 Ox Preferred Positioning with rats NOEL physical dependence: &gt; 20 mg / kg i.p. > 22 0 x &quot; *) MPE (= Maximum Possible Ef fect) indicates the dimension of maximum possible effect; NOEL (&quot; = No &quot; Observed Effect Mild) indicates the highest dose free of results (i.e., the dose without significant effect) 2) The clearance factors are calculated as the NOEL ratio and an average EDson value from models of neuropathy (in this case: 88 pg / kg)

Conclusion: To illustrate the surprising pharmacological properties of the compounds within the scope of the present invention, an example of AMD-6C1S was selected. It is a high affinity ORL-1 receptor ligand and receptor-lycopene receptor and with an ORL-1 receptor affinity ratio for the 5-or 6-receptor-opioid. Examples are MD-6c, LS and 88E 2 598 503 / ΡΤ AMD-7c bond: 1 show that the compounds within the present invention have a very high level of efficacy against neuropathic pain (here: ED50 of between 1 and 10 pg / kg iv or 88 pg / kg iv) · In contrast, no significant antinociceptive effect is observed to be significant in the acute pain model, even at doses that were 100 to 1000 times higher than that in efficient dosages in neuropathic models. Likewise, typical typical opioid side effects (such as respiratory depression, reduced blood pressure and heart rate, constipation, central nervous system effects, physical dependence, psychological dependence / abstinence) in animal models in the study of side effects even at doses ranging from 11 to more than 3000 times higher.

Table 2: Overview of pharmacological or drug-kinetic characteristics selected from other examples

Rats according to Chung Rat removal test in rats Arterial gas analysis in rats Passage with charcoal in rats RotaRod test in rat / 2 mice rats, 100 pg / kg, iv / duration of the drug-dynamic effect (Dose) AMD-6 ° "0.030 0.138 EDS0 = 9 pg / kg iv NOEL2 = 1000 pg / kg iv NOEL = 1000 pg / kg iv NOEL = 3000 pg / kg iv NOEL : 10000 pg / kg iv 8 h // »5 h (10 pg / kg iv) AMD-1 °" 0.018 0.032 18% MPE at 100 pg / kg iv NOEL> 100 pg / kg iv NOEL = 1000 pg / kg iv Not performed Not performed Not determined Not determined AMD-2 "** 0.017 0.05 35% MPE at 100 pg / kg iv NOEL> 1000 pg / kg iv Not done NOEL = 4600 pg / kg iv No (iv) AMD-3cis * 0.016 0.059 42% MPE at 100 pg / kg iv NOEL> 1000 pg / kg iv Not performed NOEL = 3000 pg / kg iv NOEL: > 10000 pg / kg iv Not determined // ca. 3 h (100 pg / kg iv) AMD-4 "s * 0.003 0.009 20% MPE at 1 100 pg / kg iv NOEL> 100 pg / kg iv NOEL = 300 pg / kg iv Not performed Not performed Not determined // 1-3 h (100 pg / kg iv) AMD-7 "s * 0.070 0.450 EDso = 88 pg / kg iv NOEL &gt; 10000 pg / kg i.v. NOEL = 1000 pg / kg i.v. NOEL = 1000 pg / kg i.v. NOEL = 10000 pg / kg i.v. 3 h.c. 3 h (100 pg / kg iv)) Affinity ratio ORL1 / μ- defined as 1 / [K1 (OHLi) / K1 (p)] 2) NOEL (= No Observed Effect Levei) indicates the highest dose free of results (i.e., the dose without significant effect) *) Reference compound

Conclusion: The compounds within the present invention exhibit very good efficacy against neuropathic pain. Surprisingly, however, no significant anti-nociceptive effects are observed in acute pain models, even at doses of approximately 10-fold to over 100-fold higher than effective dosages in a neuropathic model. Likewise and also surprisingly, there are also no significant side effects typical of opioids, in studies of side effects in animal models (eg gasometry, gastrointestinal carbon passage and RotaRod test) even at dosages of 10 to 300 times more high.

Table 3: Comparison of cis- and trans-

Rats according to Chung Tail-tailing test in rats Arterial gas analysis in AMD-6cis rats 0.030 0.138 ED50 = 9 pg / kg i.v. NOEL2 = 1000 100 μg / kg IV ED50 = 640 pg / kg iv NOEL = 300 pg / kg iv AMD-7cis * 0.070 0.450 ED50 pg / kg i NOV = 1000 pg / kg iv AMD-6trans * 0.002 0.008 NOEL = 88 pg / kg iv NOEL2> 10000 pg / kg iv NOEL = 1000 pg / kg iv AMD-7trans * 0.001 0.001 Not performed 54% MPE at 31.6 pg / kg iv Not performed AMN-2cis * 0.012 0.031 ED50 = 895 pg / kg NOEL = 1000 pg / kg Not performed AMN-2trans * 0.0004 0.0005 27% MPE at 30 pg / kg iv 60% MPE at 100 pg / kg i.p. Not performed ORL1 / μ affinity ratio - defined as 1 / [Ki (0rli) / Κι (μ)] 2) NOEL (= No Observed Effect Levei) indicates the highest dose free of results (i.e. the dose without significant effect)

Conclusion: Surprisingly, only the cis spiroamines within the scope of the present invention (in this example AMD-6C1S and AMN-2C1S compound) show good efficacy against neuropathic pain, while having a lack of antinociceptive effect on acute pain. Likewise, significant side effects typical of opioids are not observed in animal side effects models (in this case, as an example of gasometry) even in cases of several times higher dosages. Trans-relevant spiroamines (In these cases, comparative examples AMD-6trans and AMN-2trans), however, do not show any separation between dosages that are effective against neuropathic pain or acute pain. Likewise, there is no withdrawal at doses in which the typical side effects of opioids are observed (for example, blood gas analysis). Here the AMD-5C1S or AMD-6c1s in the general comparison show the 90 ΕΡ 2 598 503 / ΡΤ greater deviations in situations of greater analgesic effect possible.

Table 4: Comparison of cis spiroamines and cis spiro ethers (reference compounds)

Rats according to Chung Tail-removal test in rats or mice * AMN-2cis 0, 012 0, 031 ED50 = 895 pg / kg iv NOEL2 = 1000 pg / kg Ki (μl) kg iv Eter-2c 0.03 0.092 17% MPE at 100 pg / kg i V 78% MPE at 1000 pg / kg iv * Eter-lys 0.6 0, 12 28% MPE at 100 pg / kg i (Κ) Κ Κ Κ Κ Κ Κ Κ Κ Κ Κ Κ Κ Κ Κ Κ Κ Κ Κ Κ Κ Κ Κ Κ Κ Κ Κ Κ Κ Κ Κ 2 2 2 Κ 2 2 2 2 Κ 2 2 2 2 2 2 2 2 2 2 2 2 2 Κ 2 Κ 2 Κ 2 Κ Κ Κ Κ Κ of results (ie, the dose with no significant effect)

Conclusion: Surprisingly, only cis spiroamines such as the compounds within the scope of the present invention (in this case the comparative example AMN-2C1S) show good efficacy against neuropathic pain at the same time without antinociceptive effect on acute pain. Likewise, typical side effects of opioids are not observed even in administrations of several times higher dosages in animal side effects models (in this case as an example blood gas analysis). The cis spiroether (in this case comparative example Ether-2C1S and Ether-1s), however, does not show any significant spacing between dosages effective against neuropathic pain or acute pain.

Table 5: Comparison of AMD-5C1S (free base) and AMD-6C1S (citrate salt)

Ratio according to tail-withdrawal test [μΜ] [μΜ] Chung in AMD-5 mice "S 0, 030 0, 138 ED50 = 17 pg / kg iv NOEL 2 = 30000 pg / kg ip AMD-6 "s h -1: 0.120 0.17 ED50 = 9 pg / kg iv NOEL &gt; 10000 pg / kg iv) Affinity ratio ORL1 / μ- defined as 1 / [Ki (orld / ¾ &lt; μ)] 2) NOEL (= No Observed Effect Mild) indicates the highest dose-free dose (ie, no significant effect dose)

Conclusion: A comparison of AMD-5C1S (free base) and AMD-6C1S (citrate salt) shows no relevant differences in the pharmacological properties of base and salt. 91 ΕΡ 2 598 503 / ΡΤ

Table 6: Comparison of affinities for the different receptors ORL-1 μ-Opioid d-Opioid k Opioid Opioid Pain in rats Neuropathic (SNL [Chung]) Ki * EC50 ** Ki ECso Ki ECso Ki ECso ED 50 rats [pg / kg]% MPE (æg / kg) AMD-3cis§ 16 102/92% 59 1112/82% 160 874/42% 6, 7 41/92% 0% (1000) 106 73% (10000) AMD-3trans§ 14 16/81% 12 13/66% 49- / 55% 8- / 87% 0% (1000) 20% (100) AMD-5cis 30 76/106% 138-300 / 63% 768 1035/30% 38 463/78% 0% (1000) 9.2 58% (10000) AMD-6trans§ 3 47/104% 8 79/97% 19 59/88% 6 19/126% 640 400 AMD -7cis§ 70 50/90% 450 49/94% 542 1170/85% 791 2684/106% 0% (10000) 88 AMD-7trans§ 1 16/90% 1 3/88% 4 29/64% 1 5 / 82% 54% (31.6) Not performed * Radio - Ki binding test in nM GTPgarrunaS - EC50 assay in nM and relative efficiency in%

Ki [nM] EC50 [eff. %] §) Comparative example

Lisbon 2014-04-24

Claims (15)

A compound of general formula (III): ## STR2 ## wherein R1 is -H or CH3; R 2 is -H or -halogen; R3 is -H or -halogen; R4 is -H, -halogen or -OC4-3-alkyl; R5 is -H, -halogen or -OC4-3-alkyl; in the form of free bases, or physiologically compatible salts thereof. A compound according to claim 1, wherein R 2 is -H and / or R 3 is -F. A compound according to claim 1 or 2, wherein R 4 and R 5 are both -H or both -OCH 3. A compound according to any of the preceding claims, which is selected from the group consisting of: (E) -1 - ((1S, 4S) -4- (Dimethylamino) -4-phenyl-3 ', 4' dihydro-spiro [cyclohexane-1,1'-pyrido [3,4-b] indole] -2 '(9' H) -yl) -3-phenylprop-2-en-1-one; • (E) -1 - ((1S, 4S) -4- (dimethylamino) -4- (3-fluorophenyl) -3 ', 4'-dihydrospiro [cyclohexane-1,1'-pyrido [3 , 4-b] indole] -2 '(9H) -yl) -3-phenylprop-2-en-1-one; Î ± 2 598 503 / ΡΤ 2/3 • (Ε) -1 - ((1S, 4S) -4- (dimethylamino) -6'-fluoro-4- (3-fluoro-phenyl) -3 ', 4'- dihydrospiro [cyclohexane-1,1'-pyrido [3,4-b] indole] -2 '(9' H) -yl) -3-phenylprop-2-en-1-one; (E) -1 - ((1S, 4S) -4- (dimethylamino) -6'-fluoro-4-phenyl-3 ', 4'-dihydrospiro [cyclohexane-1,1'-pyrido [3 , 4-b] indole] -2 '(9H) -yl) -3-phenylprop-2-en-1-one; • (E) -1 - ((1S, 4S) -4- (dimethylaminoethyl) amino) -4- (4-fluoro-phenyl) -3 ', 4'-dihydrospiro [cyclohexane- -pyrido [3,4-b] indole] -2 '(9' H) -yl) -3-phenylprop-2-en-1-one; in the form of their free bases or their physiologically tolerated salts. A compound according to any one of claims 1 to 4, having the structure: / in the form of their free bases or their physiologically acceptable salts. A compound according to any one of claims 1 to 4 for use as a medicament. A pharmaceutical composition comprising a physiologically acceptable carrier and a compound according to any one of claims 1 to 5. Composition according to Claim 7, which is in solid, liquid or pasty form; The compound according to any one of claims 1 to 5 in an amount of 0.001 to 99% by weight, calculated on the basis of the total weight of the composition. A pharmaceutical dosage form, which contains the pharmaceutical composition according to claim 7 or 8. A dosage form according to claim 9, which is formulated for an administration of at most not more than once a day. A dosage form according to claim 9 or 10, which is formulated for systemic administration. A dosage form according to claim 11, which is formulated for oral administration. A dosage form according to claim 12, containing the compound according to any one of claims 1 to 5, in a dose ranging from 1.0 pg to 10 mg, calculated on the basis of the molecular weight of the free base. A compound according to any one of claims 1 to 5 for use in the treatment of neuropathic and / or chronic pain. A compound according to claim 14, wherein the administration is made at most once daily. Lisbon, 2014-04-24